Herbicidal Pyridino-/Pyrimidino-Thiazoles

ABSTRACT

The present invention relates to herbicidally active pyridino-/pyrimidino-thiazole derivatives, as well as to processes and intermediates used for the preparation of such derivatives. The invention further extends to herbicidal compositions comprising such derivatives, as well as to the use of such compounds and compositions in controlling undesirable plant growth: in particular the use in controlling weeds, in crops of useful plants.

The present invention relates to herbicidally activepyridino-/pyrimidino-thiazole derivatives, as well as to processes andintermediates used for the preparation of such derivatives. Theinvention further extends to herbicidal compositions comprising suchderivatives, as well as to the use of such compounds and compositions incontrolling undesirable plant growth: in particular the use incontrolling weeds, in crops of useful plants.

Herbicidal pyrimidino-imidazoles are known from WO2005/047281.Pyridino-/pyrimidino-thiazole derivatives, for use asacaricidal/insecticidal/molluscicidal/nematicidal agents, or incontrolling invertebrate pests, are described in WO2010/129497,WO2011/128304, WO2013/186089, and WO2014/007395.

The present invention is based on the finding that pyridino-thiazole,and pyrimidino-thiazole, derivatives of formula (I) as defined herein,exhibit surprisingly good herbicidal activity.

Thus, in a first aspect of the invention there is provided the use of acompound of formula (I)

or a salt or N-oxide thereof, wherein,X₁ is N or CR¹;R¹ is hydrogen, halogen, cyano, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C(O)OR⁶ or S(O)_(n)(C₁-C₆ alkyl),formyl, hydroxyl, —C(O)NR⁶R⁷, NR⁶R⁷, benzyloxy, C₁-C₆ haloalkoxy, orC₁-C₆ haloalkyl;R² is hydrogen, halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, —C(O)OR⁶, S(O)_(n)(C₁-C₆alkyl), C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;n is 0, 1, or 2;R³ is hydrogen, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆haloalkenyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₂-C₆alkenyloxy, C₃-C₁₀ cycloalkyl, NR⁶R⁷,R⁴ is O, S, or N(C₁-C₆ alkyl);X₂ is O, S, or NR⁸;R⁵ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkenyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy,C₃-C₁₀ cycloalkyloxy, C₃-C₁₀ cycloalkenyloxy, C₂-C₆ haloalkenyloxy,C₆-C₁₀ aryl or C₆-C₁₀ aryl substituted by from 1 to 3 groupsindependently selected from halogen, nitro, cyano, C₁-C₃ alkyl, C₁-C₃alkoxy, C₁-C₃ haloalkyl, and C₁-C₃ haloalkoxy; C₃-C₁₀ heterocyclyl orC₃-C₁₀ heterocyclyl substituted by from 1 to 3 groups independentlyselected from halogen, nitro, cyano, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃haloalkyl, and C₁-C₃ haloalkoxy; or NR⁶R⁷;or R³ and R⁵ together with X₂ and the atoms to which they are attached,form a saturated or partially unsaturated 5-9 membered ring systemoptionally comprising 1 to 3 heteroatoms independently selected from S,O and N and optionally substituted with 1 to 3 groups independentlyselected from halogen or C₁-C₆ alkyl;or R³ and R⁸ together with the atoms to which they are attached form asaturated or partially unsaturated 5-9 membered ring system optionallycomprising 1 to 3 heteroatoms independently selected from S, O and N andoptionally substituted with 1 to 3 groups independently selected fromhalogen or C₁-C₆ alkyl;or R⁴ and R⁵ together with X₂ and the atoms to which they are attached,form a saturated or partially unsaturated 5-9 membered ring systemoptionally comprising 1 to 3 heteroatoms independently selected from S,O and N and optionally substituted with 1 to 3 groups independentlyselected from halogen or C₁-C₆ alkyl; R⁶ and R⁷ are each independentlyhydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,or R⁶ and R⁷ together with the nitrogen atom to which they are attachedform a saturated or partially unsaturated 3-6 membered ring optionallycomprising 1 to 3 heteroatoms independently selected from S, O and N andoptionally substituted with 1 to 3 groups independently selected fromhalogen or C₁-C₆ alkyl;R⁸ is hydrogen, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, orC₂-C₆ alkynyl; C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₃-C₁₀ cycloalkyloxy, C₃-C₁₀ cycloalkenyloxy, C₂-C₆haloalkenyloxy;or R⁷ and R⁸ together with the carbon atoms to which they are attachedform a saturatedor partially unsaturated 3-9 membered ring optionally comprising 1 to 3heteroatoms independently selected from S, O and N and optionallysubstituted with 1 to 3 groups independently selected from halogen orC₁-C₆ alkyl, as a herbicide.

Compounds of formula (I) may exist as different geometric isomers, or indifferent tautomeric forms. This invention covers the use of all suchisomers and tautomers, and mixtures thereof in all proportions, as wellas isotopic forms such as deuterated compounds.

It may be the case that compounds of formula (I) may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry, thepresent invention includes the use of all such optical isomers anddiastereomers as well as the racemic and resolved, enantiomerically pureR and S stereoisomers and other mixtures of the R and S stereoisomersand agrochemically acceptable salts thereof.

Each alkyl moiety either alone or as part of a larger group (such asalkoxy, alkylthio, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, ordialkylaminocarbonyl, et al.) may be straight-chained or branched.Typically, the alkyl is, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,neopentyl, or n-hexyl. The alkyl groups are generally C₁-C₆ alkyl groups(except where already defined more narrowly), but are preferably C₁-C₄alkyl or C₁-C₃ alkyl groups, and, more preferably, are C₁-C₂ alkylgroups (such as methyl).

Alkenyl and alkynyl moieties can be in the form of straight or branchedchains, and the alkenyl moieties, where appropriate, can be of eitherthe (E)- or (Z)-configuration. Alkenyl and alkynyl moieties can containone or more double and/or triple bonds in any combination; butpreferably contain only one double bond (for alkenyl) or only one triplebond (for alkynyl).

The alkenyl or alkynyl moieties are typically C₂-C₄ alkenyl or C₂-C₄alkynyl, more specifically ethenyl (vinyl), prop-2-enyl (allyl),ethynyl, prop-2-ynyl (propargyl), or prop-1-ynyl.

Preferably, the term cycloalkyl refers to cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

In the context of the present specification the term “aryl” preferablymeans phenyl.

Heterocyclyl groups and heterocyclic rings (either alone or as part of alarger group, such as heterocyclyl-alkyl-) are ring systems containingat least one heteroatom and can be in mono- or bi-cyclic form.Preferably, heterocyclyl groups will contain up to two heteroatoms whichwill preferably be chosen from nitrogen, oxygen and sulfur. Examples ofheterocyclic groups include oxetanyl, thietanyl, azetidinyl and7-oxa-bicyclo[2.2.1]hept-2-yl. Heterocyclyl groups containing a singleoxygen atom as heteroatom are most preferred. The heterocyclyl groupsare preferably 3- to 8-membered, more preferably 3- to 6-membered rings.

Halogen (or halo) encompasses fluorine, chlorine, bromine or iodine. Thesame correspondingly applies to halogen in the context of otherdefinitions, such as haloalkyl or halophenyl.

Haloalkyl groups having a chain length of from 1 to 6 carbon atoms are,for example, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl,2-fluoroethyl, 2-chloroethyl, pentafluoroethyl,1,1-difluoro-2,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl and2,2,2-trichloroethyl, heptafluoro-n-propyl and perfluoro-n-hexyl.

Alkoxy groups preferably have a chain length of from 1 to 6 carbonatoms. Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy or tert-butoxy or a pentyloxy orhexyloxy isomer, preferably methoxy and ethoxy. It should also beappreciated that two alkoxy substituents may be present on the samecarbon atom.

Haloalkoxy is, for example, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy,2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy or2,2,2-trichloroethoxy, preferably difluoromethoxy, 2-chloroethoxy ortrifluoromethoxy.

C₁-C₆ alkyl-S— (alkylthio) is, for example, methylthio, ethylthio,propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio ortert-butylthio, preferably methylthio or ethylthio.

C₁-C₆ alkyl-S(O)— (alkylsulfinyl) is, for example, methylsulfinyl,ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl,isobutylsulfinyl, sec-butylsulfinyl or tert-butylsulfinyl, preferablymethylsulfinyl or ethylsulfinyl.

C₁-C₆ alkyl-S(O)₂— (alkylsulfonyl) is, for example, methylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl,isobutylsulfonyl, sec-butylsulfonyl or tert-butylsulfonyl, preferablymethylsulfonyl or ethylsulfonyl.

Compounds of formula (I) may form, and/or be used as, agronomicallyacceptable salts with amines (for example ammonia, dimethylamine andtriethylamine), alkali metal and alkaline earth metal bases orquaternary ammonium bases. Among the alkali metal and alkaline earthmetal hydroxides, oxides, alkoxides and hydrogen carbonates andcarbonates used in salt formation, emphasis is to be given to thehydroxides, alkoxides, oxides and carbonates of lithium, sodium,potassium, magnesium and calcium, but especially those of sodium,magnesium and calcium. The corresponding trimethylsulfonium salt mayalso be used.

Compounds of formula (I) may also form (and/or be used as) agronomicallyacceptable salts with various organic and/or inorganic acids, forexample, acetic, propionic, lactic, citric, tartaric, succinic, fumaric,maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic,phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic,benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly knownacceptable acids, when the compound of formula (I) contains a basicmoiety.

Compounds of formula (I) may also be in the form of/used as hydrateswhich may be formed during the salt formation.

Preferred values of X₁, X₂, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and n, areas set out below, and a compound of formula (I) according to theinvention may comprise any combination of said values. The skilledperson will appreciate that values for any specified set of embodimentsmay combined with values for any other set of embodiments where suchcombinations are not mutually exclusive.

Preferably R¹ is hydrogen, halogen, formyl, cyano, C₁-C₆ alkoxy, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, C₁-C₆ haloalkoxy, —C(O)NR⁶R⁷, NR⁶R⁷, orC₁-C₆ haloalkyl. More preferably R¹ is hydrogen, fluorine, chlorine,cyano, trifluoromethyl, methoxy, difluoromethoxy, formyl,methanesulfonyl, carboxamide, methanethiol or amino.

Preferably R² is halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₂-C₆ alkenyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, —C(O)OR⁶, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl,or C₂-C₆ alkynyl. More preferably R² is halogen, cyano, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃-C₆cycloalkyl, —C(O)OR⁶, or C₂-C₆ alkynyl. Even more preferably R² ismethyl, trifluoromethyl, chloro, bromo, iodo, fluoro, vinyl, acetylenyl,methoxycarbonyl, —CO₂H, or cyclopropyl;

Preferably R³ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆haloalkenyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₂-C₆alkenyloxy, C₃-C₁₀ cycloalkyl, or NR⁶R⁷. More preferably R³ is hydrogen,or C₁-C₃ alkyl. Even more preferably R³ is methyl or ethyl.

Preferably R⁴ is O.

Preferably X₂ is O, or NR⁸.

Preferably R⁵ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₃-C₁₀ cycloalkyloxy,C₃-C₁₀ cycloalkenyloxy, C₂-C₆ haloalkenyloxy, C₆-C₁₀ aryl, C₆-C₁₀ arylsubstituted by 1-3 groups independently selected from halogen, nitro,cyano, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkyl, and C₁-C₃ haloalkoxy,C₃-C₁₀ heterocyclyl, or NR⁶R⁷. In one set of embodiments R⁵ ispreferably methyl, ethyl, iso-propyl, tert-butyl, or tert-butoxy. In afurther set of embodiments, R⁵ is preferably phenyl optionallysubstituted by 1-3 groups halogen, nitro, cyano, C₁-C₃ alkyl, C₁-C₃alkoxy, C₁-C₃ haloalkyl, and C₁-C₃ haloalkoxy, more preferably phenylsubstituted once by halogen, nitro, cyano, C₁-C₃ alkyl, C₁-C₃ alkoxy,C₁-C₃ haloalkyl, or C₁-C₃ haloalkoxy,

In a further set of embodiments R⁵ is preferably C₂-C₆ alkynyl.Compounds of formula (I) where R⁵ is C₂-C₆ alkynyl are novel and thusform a further aspect of the invention.

Preferably R⁸ is hydrogen, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, or C₂-C₆ alkynyl. More preferably R⁸ is hydrogen or methyl. Inone set of embodiment R⁸ is hydrogen. In a further set of embodiments R⁸is methyl.

In embodiments where R³ and R⁵ together with X₂ and the atoms to whichthey are attached, form a saturated or partially unsaturated 5-9membered ring system optionally comprising 1 to 3 heteroatomsindependently selected from S, O and N and optionally substituted with 1to 3 groups independently selected from halogen or C₁-C₆ alkyl, it ispreferred that the following groups Q, are formed:

wherein X² and R⁴ are as defined herein, and A denotes the point ofattachment to the pyridino/pyrimidino-thiazole moiety. Preferably ineach of groups Q₁ and Q₂, R⁴ is O and X₂ is O or NR⁸. Even morepreferably, R⁴ is O and X₂ is O or NR⁸ and R⁸ is methyl.

Tables 1 and 2 below provide 91 specific examples of herbicidalcompounds of formula (I) for use according to the invention.

TABLE 1 Specific examples of compounds of formula (I) Compound StructureA1 

A2 

A3 

A4 

A5 

A6 

A7 

A8 

A9 

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A38

A39

A40

A41

A43

A44

A45

A46

A47

A48

A49

A50

A51

A52

A53

A54

A55

A56

A57

A58

A59

A60

A61

A62

A63

As stated hereinbefore, compounds of formula (I) wherein R⁵ is C₂-C₆alkynyl are novel. Accordingly, the invention also provided compounds offormula (I)-(i), which are compounds of formula (I) as defined herein,wherein R⁵ is C₂-C₆ alkynyl. In compounds of formula (I)-(i) thepreferred substituents for X₁, X₂, R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and n areas defined hereinbefore, with respect to compounds of formula (I)

However, particularly preferred embodiments will have the substituentpreferences described below.

Where X₁ is CR¹, R¹ is preferably halogen, more preferably fluoro. R² ispreferably methyl, trifluoromethyl, chloro, bromo, iodo, fluoro, vinyl,acetylenyl, methoxycarbonyl, —CO₂H, or cyclopropyl, more preferablymethyl. R³ is preferably hydrogen or C₁-C₃ alkyl, more preferably methylor ethyl, most preferably methyl. R⁴ is preferably oxygen. X₂ ispreferably oxygen or NR⁸, wherein R⁸ is preferably hydrogen. R⁵ ispreferably C₃-C₅ alkynyl.

In one particularly preferred set of embodiments, R⁵ is selected fromthe group consisting of 1-methyl-prop-2-ynyl, 1,1-dimethylprop-2-ynyl,and prop-2-ynyl. Table 2 below provides 28 specific examples ofcompounds of formula (I)-(i) according to the invention.

TABLE 2 Specific examples of compounds of formula (I)-(i) CompoundStructure B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

B20

B21

B22

B23

B24

B25

B26

B27

B28

Compounds of formula (I) may be prepared according to the followingschemes, in which the substituents X₁, X₂, R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, and n, have (unless otherwise stated explicitly) the definitionsdescribed hereinbefore, using techniques known to the person skilled inthe art of organic chemistry. General methods for the production ofcompounds of formula (I) are described below. Unless otherwise stated inthe text the synthetic procedures are derived from WO2013/186089 orW2010/129497. The starting materials used for the preparation of thecompounds of the invention may be purchased from the usual commercialsuppliers or may be prepared by known methods. The starting materials aswell as the intermediates may be purified before use in the next step bystate of the art methodologies such as chromatography, crystallization,distillation and filtration.

Typical abbreviations used throughout are as follows:

Ac=acetylBn=benzylBu=butylt-BuOH=tert-butanolDMAP=4-dimethylaminopyridine

DMF=N, N-dimethylformamide

DMSO=dimethylsulfoxideDPPA=diphenylphosphoryl azideEt₃N=triethylamineEt₂O=diethyl etherEtOAc=ethyl acetateEtOH=ethanolmCPBA=meta-chloro-benzoic acidMe=methylMeI=methyl iodideMeCN=acetonitrile

NBS=N-bromosuccinimide

N-Boc=N-tert-butoxycarbony

NIS=N-odosuccnmde

Ph=phenylTFA=trifluoroacetic acidTHF=tetrahydrofuran

As shown in Reaction Scheme 1, compounds of formula (I) can be preparedvia a three step sequence wherein a suitably substituted2-bromo-thiazole-5-carboxylic acid (II) can be reacted to form an acylazide with suitable reagents such as diphenylphosphoryl azide (DPPA)which can be further converted in-situ with a suitable alcohol, such ast-butanol (t-BuOH) to give the carbamates of formula (III). This can befurther substituted with alkylating agents such as MeI under basicconditions (for example using NaH) in a polar solvent (such as DMF) togive compounds of formula (IV). These compounds can be converted toproducts of formula (I) using palladium catalysed cross-coupling betweena suitable boronic acid derivative of formula (V) with a palladiumcatalyst such as Pd(PPh₃)₄, a base such as potassium carbonate and asolvent which may be a mixed solvent system such as ethanol, toluene andwater.

Alternatively (as also shown in reaction scheme 1) compounds of formula(I) can be prepared via variation of the three step sequence wherein asuitably substituted 2-bromo-thiazole-5-carboxylic acid (II) can bereacted to form an acyl azide with suitable reagents such asdiphenylphosohoryl azide (DPPA) which can be further converted in-situwith a suitable alcohol, such as t-Butanol (t-BuOH) to give thecarbamates of formula (III).

These compounds can be converted to products of formula (Ia) usingpalladium catalysed cross-coupling between a suitable boronic acidderivative of formula (V) with a palladium catalyst such as Pd(PPh₃)₄, abase such as potassium carbonate and a solvent which may be a mixedsolvent system such as ethanol, toluene and water. These materials canbe further reacted with alkylating agents such as MeI under basicconditions (for example using NaH) with a polar solvent (such as DMF) togive compounds of formula (I).

Compounds of formula (I) may also be prepared via condensation of anappropriately substituted thioamide (VI) in the presence of anappropriately substituted 2-halo β-keto ester (VII), for example whereR²=alkyl or trifluoroalkyl, to give compounds of formula (VIII) whichcan be further elaborated via basic saponification, for example withNaOH, water and ethanol mixtures. The resulting carboxylic acid (IX) canbe reacted to form an acyl azide with suitable reagents such asdiphenylphosphoryl azide (DPPA), which can be further converted in-situwith a suitable alcohol, such as t-butanol (t-BuOH), to give thecarbamates of formula (Ia). These materials can be further reacted withalkylating agents such as MeI under basic conditions, for example usingK₂CO₃ in a polar solvent (such as MeCN), to give compounds of formula(I) (Reaction Scheme 2).

As shown in Reaction Scheme 3, when R⁴ is O, X₂ is O and R⁵ is t-Bu, theresulting N-Boc group may be removed under mild acidic conditions, suchas with HCl in ether, to afford an amine salt, such as the HCl salt.Compounds of formula (X) may then be further converted to compounds suchas (Ic) by reaction with a suitable chloroformate (such as ethylchloroformate) and a base such as pyridine.

Alternatively, compounds of formula (X) may then be further converted tocompounds such as (Id) by reaction with a suitable isocyanate (such ast-butyl-isocyanate). Compounds of formula (Id) may be further alkylatedwith a suitable electrophile and base combination (for example MeI,K₂CO₃) to give compounds of the type where X₂=NR⁸ (Ie).

As a further alternative, compounds of formula (X) may then be furtherconverted to compounds of Formula (XI) by reaction with a compound ofFormula (XXX), where Lg is a suitable leaving group (such as Cl); forexample phosgene or a suitable phosgene equivalent (such ascarbonyldiimidazole or 4-nitrophenyl chloroformate). This may befollowed by reaction with an alcohol, amine or thiol to afford compoundsof formula (I).

In cases where R² is H, it is possible to convert compounds of Formula(If) into compounds of Formula (Ig) by alkylation of the nitrogen usinga base, such as NaH, and an electrophile, such as MeI, in a polarsolvent, such as DMF. It is then possible perform electrophilicsubstitution to introduce new R² substituents on compound (Ig).Electrophilic halogenation reagents can be used to perform thistransformation. For example where R² is I, N-iodosuccinimide in asolvent such as acetonitrile are suitable conditions to give a compoundof formula (Ii). Where R² is Br, N-bromosuccinimide in a solvent (e.g.acetonitrile) is suitable to give a compound of formula (Ij), and whereR² is Cl, N-chlorosuccinimide in a solvent (e.g. acetonitrile) can beused to furnish a compound of formula (Ik). Where R² is F, Selectfluor™(1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate) in acetonitrile is a typical set of reactionconditions to perform the transformation to convert a compound offormula (Ig) into a compound of formula (Ih) (Reaction Scheme 4, above).

Compounds of formula (I) may also be prepared via condensation of anappropriately substituted thioamide (VI) in the presence of anappropriately substituted 2-halo ketone (XII) (e.g. chloroacetone) togive compounds of formula (XIII), which can be further elaborated viahalogenation (for example with NBS) to afford the bromo-thiazole (XIV).

Reaction of compounds of this type with a nitrogen containingheterocycle, such as a hydantoin of formula (XV), in the presence of acopper catalyst (e.g. CuI) with a base (e.g. K₂CO₃) with a ligand (e.g.N,N′-dimethylethylenediamine (XVI)) in a suitable solvent (e.g.1,4-dioxane) affords compounds of formula (Im). This is shownschematically in Reaction Scheme 5 (above), and typical methods for sucha transformation are taught, for example, in WO2011/136292).

Compounds of formula (X) can be converted to a compound of formula (In)by treatment with a bifuctional reagent (XVII) (such as1-chloro-2-isothiocyanoethane) in a solvent (such as dioxane) as taughtin WO2013/186089 (Reaction Scheme 6).

Acylation of a compound of formula (Ia) with a bifuctional reagent(XVIII) (e.g. chloroethyl chloroformate) with a base (e.g sodiumhydride) in an ethereal solvent (e.g. THF) affords compounds of formula(Io). The N-Boc group can be removed under mild conditions with reagentssuch as TFA in CH₂Cl₂ to give (Ip).

Further compounds of formula (Ip) can be cyclized by deprotonation witha suitable base (such as NaH) in a polar solvent (DMF is a suitablesolvent for this step) to give compound of formula (Iq) (Reaction Scheme7).

Iodinated compounds of formula (Ir) can themselves be useful buildingblock to allow easy access to compounds of formulae (Is)-(Ix) (ReactionScheme 8). Compound (Is) can be prepared by Iodine-Lithium exchange(using a reagent such as n-BuLi) followed by quenching with CO₂ in anethereal solvent (such as THF).

Compounds of Formula (It) can be prepared by Iodine-Lithium exchange(using a reagent such as n-BuLi) followed by quenching with achloroformate (such as methyl chloroformate) in an ethereal solvent(such as THF).

Compounds of formula (Iu) can be made via a Stille cross-coupling with aPd catalyst (such as Pd(PPh₃)₂Cl₂) in a suitable solvent (such as1,4-dioxane) with a suitable stannane (such as (XIX)).

Compounds of formula (Iv) can be made via a Stille cross-coupling with aPd catalyst (such as Pd(PPh₃)₂Cl₂) in a suitable solvent (such as1,4-dioxane) with a suitable stannane (such as (XX)).

Compounds of formula (Iw) can be made via a Suzuki cross-coupling with aPd pre-catalyst (such as Pd(OAc)₂), with a suitable ligand (such asP(c-hexyl)₃) and base (such as K₃PO₄) in a suitable solvent such as1,4-dioxane with a suitable boronic acid (such as (XXI)).

Reaction of compounds of Formula (X) with carbon disulphide in a solventsuch as ethanol and a base such as K₂CO₃, followed by addition of anelectrophile such as an alkyl iodide gives compounds of formula (Iaa)(Reaction Scheme 9).

Compounds of formula (Iab) where X₂ is O and R⁵ is alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl or haloalkenyl, can be madevia in-situ generation of an isocyanate from a hydroxamic acid anhydride(XXV) (for example N-boc-O-tosyl hydroxylamine wherein R⁴ is O, X₂ is Oand R⁵ is t-Bu) in the presence of a base (for example K₂CO₃) via aLossen rearrangement (as taught by Thambidurai et al., TetrahedronLetters, 2012, 53, 2292 and Tetrahedron Letters, 2014, 55, 2014) whichwill then react with the amino-heterocycle of formula (X) to form thesubstituted urea compound (Iab) (Reaction Scheme 10).

Further, N-oxides of formula (Iac) may be prepared by oxidation of (I)with an oxidising agent such as meta-chloroperbenzoic acid (mCPBA) orother suitable oxidants, in a suitable solvent (for example CH₂Cl₂)(Reaction Scheme 11).

It can be seen from the general methods described above, as well as fromthe specific examples, that certain compounds of Formula (I) are notonly useful as herbicides per se, but may also be used as intermediatesin the production of further herbicidal compounds of formula (I). Thisis particularly the case for compounds of formula (I) wherein R³ ishydrogen, and/or R² is iodo.

The compounds of Formula (I) as described herein may be used asherbicides by themselves, but they are generally formulated intoherbicidal compositions using formulation adjuvants, such as carriers,solvents and surface-active agents (SFAs). Thus, the present inventionfurther provides a herbicidal composition comprising a herbicidalcompound as described herein and an agriculturally acceptableformulation adjuvant. The composition can be in the form of concentrateswhich are diluted prior to use, although ready-to-use compositions canalso be made. The final dilution is usually made with water, but can bemade instead of, or in addition to, water, with, for example, liquidfertilisers, micronutrients, biological organisms, oil or solvents.

Such herbicidal compositions generally comprise from 0.1 to 99% byweight, especially from 0.1 to 95% by weight of compounds of Formula (I)and from 1 to 99.9% by weight of a formulation adjuvant, whichpreferably includes from 0 to 25% by weight of a surface-activesubstance.

The compositions can be chosen from a number of formulation types, manyof which are known from the Manual on Development and Use of FAOSpecifications for Plant Protection Products, 5th Edition, 1999. Theseinclude dustable powders (DP), soluble powders (SP), water solublegranules (SG), water dispersible granules (WG), wettable powders (WP),granules (GR) (slow or fast release), soluble concentrates (SL), oilmiscible liquids (OL), ultra low volume liquids (UL), emulsifiableconcentrates (EC), dispersible concentrates (DC), emulsions (both oil inwater (EW) and water in oil (EO)), micro-emulsions (ME), suspensionconcentrates (SC), aerosols, capsule suspensions (CS) and seed treatmentformulations. The formulation type chosen in any instance will dependupon the particular purpose envisaged and the physical, chemical andbiological properties of the compound of Formula (I).

Dustable powders (DP) may be prepared by mixing a compound of Formula(I) with one or more solid diluents (for example natural clays, kaolin,pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk,diatomaceous earths, calcium phosphates, calcium and magnesiumcarbonates, sulphur, lime, flours, talc and other organic and inorganicsolid carriers) and mechanically grinding the mixture to a fine powder.

Soluble powders (SP) may be prepared by mixing a compound of Formula (I)with one or more water-soluble inorganic salts (such as sodiumbicarbonate, sodium carbonate or magnesium sulphate) or one or morewater-soluble organic solids (such as a polysaccharide) and, optionally,one or more wetting agents, one or more dispersing agents or a mixtureof said agents to improve water dispersibility/solubility. The mixtureis then ground to a fine powder. Similar compositions may also begranulated to form water soluble granules (SG).

Wettable powders (WP) may be prepared by mixing a compound of Formula(I) with one or more solid diluents or carriers, one or more wettingagents and, preferably, one or more dispersing agents and, optionally,one or more suspending agents to facilitate the dispersion in liquids.The mixture is then ground to a fine powder. Similar compositions mayalso be granulated to form water dispersible granules (WG).

Granules (GR) may be formed either by granulating a mixture of acompound of Formula (I) and one or more powdered solid diluents orcarriers, or from pre-formed blank granules by absorbing a compound ofFormula (I) (or a solution thereof, in a suitable agent) in a porousgranular material (such as pumice, attapulgite clays, fuller's earth,kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing acompound of Formula (I) (or a solution thereof, in a suitable agent) onto a hard core material (such as sands, silicates, mineral carbonates,sulphates or phosphates) and drying if necessary. Agents which arecommonly used to aid absorption or adsorption include solvents (such asaliphatic and aromatic petroleum solvents, alcohols, ethers, ketones andesters) and sticking agents (such as polyvinyl acetates, polyvinylalcohols, dextrins, sugars and vegetable oils). One or more otheradditives may also be included in granules (for example an emulsifyingagent, wetting agent or dispersing agent).

Dispersible Concentrates (DC) may be prepared by dissolving a compoundof Formula (I) in water or an organic solvent, such as a ketone, alcoholor glycol ether. These solutions may contain a surface active agent (forexample to improve water dilution or prevent crystallisation in a spraytank).

Emulsifiable concentrates (EC) or oil-in-water emulsions (EW) may beprepared by dissolving a compound of Formula (I) in an organic solvent(optionally containing one or more wetting agents, one or moreemulsifying agents or a mixture of said agents). Suitable organicsolvents for use in ECs include aromatic hydrocarbons (such asalkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100,SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a Registered Trade Mark),ketones (such as cyclohexanone or methylcyclohexanone) and alcohols(such as benzyl alcohol, furfuryl alcohol or butanol),N-alkylpyrrolidones (such as N-methylpyrrolidone or N-octylpyrrolidone),dimethyl amides of fatty acids (such as C₈-C₁₀ fatty acid dimethylamide)and chlorinated hydrocarbons. An EC product may spontaneously emulsifyon addition to water, to produce an emulsion with sufficient stabilityto allow spray application through appropriate equipment.

Preparation of an EW involves obtaining a compound of Formula (I) eitheras a liquid (if it is not a liquid at room temperature, it may be meltedat a reasonable temperature, typically below 70° C.) or in solution (bydissolving it in an appropriate solvent) and then emulsifying theresultant liquid or solution into water containing one or more SFAs,under high shear, to produce an emulsion. Suitable solvents for use inEWs include vegetable oils, chlorinated hydrocarbons (such aschlorobenzenes), aromatic solvents (such as alkylbenzenes oralkylnaphthalenes) and other appropriate organic solvents which have alow solubility in water.

Microemulsions (ME) may be prepared by mixing water with a blend of oneor more solvents with one or more SFAs, to produce spontaneously athermodynamically stable isotropic liquid formulation. A compound ofFormula (I) is present initially in either the water or the solvent/SFAblend. Suitable solvents for use in MEs include those hereinbeforedescribed for use in in ECs or in EWs. An ME may be either anoil-in-water or a water-in-oil system (which system is present may bedetermined by conductivity measurements) and may be suitable for mixingwater-soluble and oil-soluble pesticides in the same formulation. An MEis suitable for dilution into water, either remaining as a microemulsionor forming a conventional oil-in-water emulsion.

Suspension concentrates (SC) may comprise aqueous or non-aqueoussuspensions of finely divided insoluble solid particles of a compound ofFormula (I). SCs may be prepared by ball or bead milling the solidcompound of Formula (I) in a suitable medium, optionally with one ormore dispersing agents, to produce a fine particle suspension of thecompound. One or more wetting agents may be included in the compositionand a suspending agent may be included to reduce the rate at which theparticles settle. Alternatively, a compound of Formula (I) may be drymilled and added to water, containing agents hereinbefore described, toproduce the desired end product.

Aerosol formulations comprise a compound of Formula (I) and a suitablepropellant (for example n-butane). A compound of Formula (I) may also bedissolved or dispersed in a suitable medium (for example water or awater miscible liquid, such as n-propanol) to provide compositions foruse in non-pressurised, hand-actuated spray pumps.

Capsule suspensions (CS) may be prepared in a manner similar to thepreparation of EW formulations but with an additional polymerisationstage such that an aqueous dispersion of oil droplets is obtained, inwhich each oil droplet is encapsulated by a polymeric shell and containsa compound of Formula (I) and, optionally, a carrier or diluenttherefor. The polymeric shell may be produced by either an interfacialpolycondensation reaction or by a coacervation procedure. Thecompositions may provide for controlled release of the compound ofFormula (I) and they may be used for seed treatment. A compound ofFormula (I) may also be formulated in a biodegradable polymeric matrixto provide a slow, controlled release of the compound.

The composition may include one or more additives to improve thebiological performance of the composition, for example by improvingwetting, retention or distribution on surfaces; resistance to rain ontreated surfaces; or uptake or mobility of a compound of Formula (I).Such additives include surface active agents (SFAs), spray additivesbased on oils, for example certain mineral oils or natural plant oils(such as soy bean and rape seed oil), and blends of these with otherbio-enhancing adjuvants (ingredients which may aid or modify the actionof a compound of Formula (I)).

Wetting agents, dispersing agents and emulsifying agents may be SFAs ofthe cationic, anionic, amphoteric or non-ionic type.

Suitable SFAs of the cationic type include quaternary ammonium compounds(for example cetyltrimethyl ammonium bromide), imidazolines and aminesalts.

Suitable anionic SFAs include alkali metals salts of fatty acids, saltsof aliphatic monoesters of sulphuric acid (for example sodium laurylsulphate), salts of sulphonated aromatic compounds (for example sodiumdodecylbenzenesulphonate, calcium dodecylbenzenesulphonate,butylnaphthalene sulphonate and mixtures of sodium di-isopropyl- andtri-isopropyl-naphthalene sulphonates), ether sulphates, alcohol ethersulphates (for example sodium laureth-3-sulphate), ether carboxylates(for example sodium laureth-3-carboxylate), phosphate esters (productsfrom the reaction between one or more fatty alcohols and phosphoric acid(predominately mono-esters) or phosphorus pentoxide (predominatelydi-esters), for example the reaction between lauryl alcohol andtetraphosphoric acid; additionally these products may be ethoxylated),sulphosuccinamates, paraffin or olefine sulphonates, taurates andlignosulphonates.

Suitable SFAs of the amphoteric type include betaines, propionates andglycinates.

Suitable SFAs of the non-ionic type include condensation products ofalkylene oxides, such as ethylene oxide, propylene oxide, butylene oxideor mixtures thereof, with fatty alcohols (such as oleyl alcohol or cetylalcohol) or with alkylphenols (such as octylphenol, nonylphenol oroctylcresol); partial esters derived from long chain fatty acids orhexitol anhydrides; condensation products of said partial esters withethylene oxide; block polymers (comprising ethylene oxide and propyleneoxide); alkanolamides; simple esters (for example fatty acidpolyethylene glycol esters); amine oxides (for example lauryl dimethylamine oxide); and lecithins.

Suitable suspending agents include hydrophilic colloids (such aspolysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose)and swelling clays (such as bentonite or attapulgite).

Herbicidal compositions as described herein may further comprise atleast one additional pesticide. For example, the compounds of formula(I) can also be used in combination with other herbicides or plantgrowth regulators. In a preferred embodiment the additional pesticide isa herbicide and/or herbicide safener. Examples of such mixtures are, inwhich ‘I’ represents a compound of Formula (I), I+acetochlor,I+acifluorfen, I+acifluorfen-sodium, I+aclonifen, I+acrolein,I+alachlor, I+alloxydim, I+ametryn, I+amicarbazone, I+amidosulfuron,I+aminopyralid, I+amitrole, I+anilofos, I+asulam, I+atrazine,I+azafenidin, I+azimsulfuron, I+BCPC, I+beflubutamid, I+benazolin,I+bencarbazone, I+benfluralin, I+benfuresate, I+bensulfuron,I+bensulfuron-methyl, I+bensulide, I+bentazone, I+benzfendizone,I+benzobicyclon, I+benzofenap, I+bicyclopyrone, I+bifenox, I+bilanafos,I+bispyribac, I+bispyribac-sodium, I+borax, I+bromacil, I+bromobutide,I+bromoxynil, I+butachlor, I+butamifos, I+butralin, I+butroxydim,I+butylate, I+cacodylic acid, I+calcium chlorate, I+cafenstrole,I+carbetamide, I+carfentrazone, I+carfentrazone-ethyl, I+chlorflurenol,I+chlorflurenol-methyl, I+chloridazon, I+chlorimuron,I+chlorimuron-ethyl, I+chloroacetic acid, I+chlorotoluron,I+chlorpropham, I+chlorsulfuron, I+chlorthal, I+chlorthal-dimethyl,I+cinidon-ethyl, I+cinmethylin, I+cinosulfuron, I+cisanilide,I+clethodim, I+clodinafop, I+clodinafop-propargyl, I+clomazone,I+clomeprop, I+clopyralid, I+cloransulam, I+cloransulam-methyl,I+cyanazine, I+cycloate, I+cyclosulfamuron, I+cycloxydim, I+cyhalofop,I+cyhalofop-butyl, I+2,4-D, I+daimuron, I+dalapon, I+dazomet, I+2,4-DB,I+I+desmedipham, I+dicamba, I+dichlobenil, I+dichlorprop,I+dichlorprop-P, I+diclofop, I+diclofop-methyl, I+diclosulam,I+difenzoquat, I+difenzoquat metilsulfate, I+diflufenican,I+diflufenzopyr, I+dimefuron, I+dimepiperate, I+dimethachlor,I+dimethametryn, I+dimethenamid, I+dimethenamid-P, I+dimethipin,I+dimethylarsinic acid, I+dinitramine, I+dinoterb, I+diphenamid,I+dipropetryn, I+diquat, I+diquat dibromide, I+dithiopyr, I+diuron,I+endothal, I+EPTC, I+esprocarb, I+ethalfluralin, I+ethametsulfuron,I+ethametsulfuron-methyl, I+ethephon, I+ethofumesate, I+ethoxyfen,I+ethoxysulfuron, I+etobenzanid, I+fenoxaprop-P, I+fenoxaprop-P-ethyl,I+fentrazamide, I+ferrous sulfate, I+flamprop-M, I+flazasulfuron,I+florasulam, I+fluazifop, I+fluazifop-butyl, I+fluazifop-P,I+fluazifop-P-butyl, I+fluazolate, I+flucarbazone,I+flucarbazone-sodium, I+flucetosulfuron, I+fluchloralin, I+flufenacet,I+flufenpyr, I+flufenpyr-ethyl, I+flumetralin, I+flumetsulam,I+flumiclorac, I+flumiclorac-pentyl, I+flumioxazin, I+flumipropin,I+fluometuron, I+fluoroglycofen, I+fluoroglycofen-ethyl, I+fluoxaprop,I+flupoxam, I+flupropacil, I+flupropanate, I+flupyrsulfuron,I+flupyrsulfuron-methyl-sodium, I+flurenol, I+fluridone,I+flurochloridone, I+fluroxypyr, I+flurtamone, I+fluthiacet,I+fluthiacet-methyl, I+fomesafen, I+foramsulfuron, I+fosamine,I+glufosinate, I+glufosinate-ammonium, I+glyphosate, I+halauxifen,I+halosulfuron, I+halosulfuron-methyl, I+haloxyfop, I+haloxyfop-P,I+hexazinone, I+imazamethabenz, I+imazamethabenz-methyl, I+imazamox,I+imazapic, I+imazapyr, I+imazaquin, I+imazethapyr, I+imazosulfuron,I+indanofan, I+indaziflam, I+iodomethane, I+iodosulfuron,I+iodosulfuron-methyl-sodium, I+ioxynil, I+isoproturon, I+isouron,I+isoxaben, I+isoxachlortole, I+isoxaflutole, I+isoxapyrifop,I+karbutilate, I+lactofen, I+lenacil, I+linuron, I+mecoprop,I+mecoprop-P, I+mefenacet, I+mefluidide, I+mesosulfuron,I+mesosulfuron-methyl, I+mesotrione, I+metam, I+metamifop, I+metamitron,I+metazachlor, I+methabenzthiazuron, I+methazole, I+methylarsonic acid,I+methyldymron, I+methyl isothiocyanate, I+metolachlor, I+S-metolachlor,I+metosulam, I+metoxuron, I+metribuzin, I+metsulfuron,I+metsulfuron-methyl, I+molinate, I+monolinuron, I+naproanilide,I+napropamide, I+naptalam, I+neburon, I+nicosulfuron, I+n-methylglyphosate, I+nonanoic acid, I+norflurazon, I+oleic acid (fatty acids),I+orbencarb, I+orthosulfamuron, I+oryzalin, I+oxadiargyl, I+oxadiazon,I+oxasulfuron, I+oxaziclomefone, I+oxyfluorfen, I+paraquat, I+paraquatdichloride, I+pebulate, I+pendimethalin, I+penoxsulam,I+pentachlorophenol, I+pentanochlor, I+pentoxazone, I+pethoxamid,I+phenmedipham, I+picloram, I+picolinafen, I+pinoxaden, I+piperophos,I+pretilachlor, I+primisulfuron, I+primisulfuron-methyl, I+prodiamine,I+profoxydim, I+prohexadione-calcium, I+prometon, I+prometryn,I+propachlor, I+propanil, I+propaquizafop, I+propazine, I+propham,I+propisochlor, I+propoxycarbazone, I+propoxycarbazone-sodium,I+propyzamide, I+prosulfocarb, I+prosulfuron, I+pyraclonil,I+pyraflufen, I+pyraflufen-ethyl, I+pyrasulfotole, I+pyrazolynate,I+pyrazosulfuron, I+pyrazosulfuron-ethyl, I+pyrazoxyfen, I+pyribenzoxim,I+pyributicarb, I+pyridafol, I+pyridate, I+pyriftalid, I+pyriminobac,I+pyriminobac-methyl, I+pyrimisulfan, I+pyrithiobac,I+pyrithiobac-sodium, I+pyroxasulfone, I+pyroxsulam, I+quinclorac,I+quinmerac, I+quinoclamine, I+quizalofop, I+quizalofop-P,I+rimsulfuron, I+saflufenacil, I+sethoxydim, I+siduron, I+simazine,I+simetryn, I+sodium chlorate, I+sulcotrione, I+sulfentrazone,I+sulfometuron, I+sulfometuron-methyl, I+sulfosate, I+sulfosulfuron,I+sulfuric acid, I+tebuthiuron, I+tefuryltrione, I+tembotrione,I+tepraloxydim, I+terbacil, I+terbumeton, I+terbuthylazine, I+terbutryn,I+thenylchlor, I+thiazopyr, I+thifensulfuron, I+thiencarbazone,I+thifensulfuron-methyl, I+thiobencarb, I+topramezone, I+tralkoxydim,I+tri-allate, I+triasulfuron, I+triaziflam, I+tribenuron,I+tribenuron-methyl, I+triclopyr, I+trietazine, I+trifloxysulfuron,I+trifloxysulfuron-sodium, I+trifluralin, I+triflusulfuron,I+triflusulfuron-methyl, I+trihydroxytriazine, I+trinexapac-ethyl,I+tritosulfuron,I+[3-[2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]aceticacid ethyl ester (CAS RN 353292-31-6). The compounds of formula (I)and/or compositions of the present invention may also be combined withherbicidal compounds disclosed in WO06/024820 and/or WO07/096576.

The mixing partners of the compound of Formula (I) may also be in theform of esters or salts, as mentioned e.g. in The Pesticide Manual,Sixteenth Edition, British Crop Protection Council, 2012.

The compound of Formula (I) can also be used in mixtures with otheragrochemicals such as fungicides, nematicides or insecticides, examplesof which are given in The Pesticide Manual (supra).

The mixing ratio of the compound of Formula (I) to the mixing partner ispreferably from 1:100 to 1000:1.

The mixtures can advantageously be used in the above-mentionedformulations (in which case “active ingredient” relates to therespective mixture of compound of Formula I with the mixing partner).

The compounds of Formula (I) as described herein can also be used incombination with one or more safeners. Likewise, mixtures of a compoundof Formula (I) as described herein with one or more further herbicidescan also be used in combination with one or more safeners. The safenerscan be AD 67 (MON 4660), benoxacor, cloquintocet-mexyl, cyprosulfamide(CAS RN 221667-31-8), dichlormid, fenchlorazole-ethyl, fenclorim,fluxofenim, furilazole and the corresponding R isomer, isoxadifen-ethyl,mefenpyr-diethyl, oxabetrinil,N-isopropyl-4-(2-methoxy-benzoylsulfamoyl)-benzamide (CAS RN221668-34-4). Other possibilities include safener compounds disclosedin, for example, EP0365484 e.gN-(2-methoxybenzoyl)-4-[(methylaminocarbonyl)amino]benzenesulfonamide.Particularly preferred are mixtures of a compound of Formula I withcyprosulfamide, isoxadifen-ethyl, cloquintocet-mexyl and/orN-(2-methoxybenzoyl)-4-[(methyl-aminocarbonyl)amino]benzenesulfonamide.

The safeners of the compound of Formula (I) may also be in the form ofesters or salts, as mentioned e.g. in The Pesticide Manual (supra). Thereference to cloquintocet-mexyl also applies to a lithium, sodium,potassium, calcium, magnesium, aluminium, iron, ammonium, quaternaryammonium, sulfonium or phosphonium salt thereof as disclosed in WO02/34048, and the reference to fenchlorazole-ethyl also applies tofenchlorazole, etc.

Preferably the mixing ratio of compound of Formula (I) to safener isfrom 100:1 to 1:10, especially from 20:1 to 1:1.

The mixtures can advantageously be used in the above-mentionedformulations (in which case “active ingredient” relates to therespective mixture of compound of Formula (I) with the safener).

As described above, compounds of formula (I) and/or compositionscomprising such compounds may be used in methods of controlling unwantedplant growth, and in particular in controlling unwanted plant growth incrops of useful plants. Thus, the present invention further provides amethod of selectively controlling weeds at a locus comprising cropplants and weeds, wherein the method comprises application to the locus,of a weed-controlling amount of a compound of formula (I), or acomposition as described herein. ‘Controlling’ means killing, reducingor retarding growth or preventing or reducing germination. Generally theplants to be controlled are unwanted plants (weeds). ‘Locus’ means thearea in which the plants are growing or will grow.

The rates of application of compounds of Formula (I) may vary withinwide limits and depend on the nature of the soil, the method ofapplication (pre- or post-emergence; seed dressing; application to theseed furrow; no tillage application etc.), the crop plant, the weed(s)to be controlled, the prevailing climatic conditions, and other factorsgoverned by the method of application, the time of application and thetarget crop. The compounds of Formula I according to the invention aregenerally applied at a rate of from 10 to 2000 g/ha, especially from 50to 1000 g/ha.

The application is generally made by spraying the composition, typicallyby tractor mounted sprayer for large areas, but other methods such asdusting (for powders), drip or drench can also be used.

Useful plants in which the composition according to the invention can beused include crops such as cereals, for example barley and wheat,cotton, oilseed rape, sunflower, maize, rice, soybeans, sugar beet,sugar cane and turf.

Crop plants can also include trees, such as fruit trees, palm trees,coconut trees or other nuts. Also included are vines such as grapes,fruit bushes, fruit plants and vegetables.

Crops are to be understood as also including those crops which have beenrendered tolerant to herbicides or classes of herbicides (e.g. ALS-,GS-, EPSPS-, PPO-, ACCase- and HPPD-inhibitors) by conventional methodsof breeding or by genetic engineering. An example of a crop that hasbeen rendered tolerant to imidazolinones, e.g. imazamox, by conventionalmethods of breeding is Clearfield® summer rape (canola). Examples ofcrops that have been rendered tolerant to herbicides by geneticengineering methods include e.g. glyphosate- and glufosinate-resistantmaize varieties commercially available under the trade namesRoundupReady® and LibertyLink®, as well as those where the crop planthas been engineered to over-express homogentisate solanesyltransferaseas taught in, for example, WO2010/029311.

Crops are also to be understood as being those which have been renderedresistant to harmful insects by genetic engineering methods, for exampleBt maize (resistant to European corn borer), Bt cotton (resistant tocotton boll weevil) and also Bt potatoes (resistant to Colorado beetle).Examples of Bt maize are the Bt 176 maize hybrids of NK® (SyngentaSeeds). The Bt toxin is a protein that is formed naturally by Bacillusthuringiensis soil bacteria. Examples of toxins, or transgenic plantsable to synthesise such toxins, are described in EP-A-451 878, EP-A-374753, WO 93/07278, WO 95/34656, WO 03/052073 and EP-A-427 529. Examplesof transgenic plants comprising one or more genes that code for aninsecticidal resistance and express one or more toxins are KnockOut®(maize), Yield Gard® (maize), NuCOTIN33B® (cotton), Bollgard® (cotton),NewLeaf® (potatoes), NatureGard® and Protexcta®. Plant crops or seedmaterial thereof can be both resistant to herbicides and, at the sametime, resistant to insect feeding (“stacked” transgenic events). Forexample, seed can have the ability to express an insecticidal Cry3protein while at the same time being tolerant to glyphosate.

Crops are also to be understood to include those which are obtained byconventional methods of breeding or genetic engineering and containso-called output traits (e.g. improved storage stability, highernutritional value and improved flavour).

Other useful plants include turf grass for example in golf-courses,lawns, parks and roadsides, or grown commercially for sod, andornamental plants such as flowers or bushes.

The compositions can be used to control unwanted plants (collectively,‘weeds’). The weeds to be controlled include both monocotyledonous (e.g.grassy) species, for example: Agrostis, Alopecurus, Avena, Brachiaria,Bromus, Cenchrus, Cyperus, Digitaria, Echinochloa, Eleusine, Lolium,Monochoria, Rottboellia, Sagittaria, Scirpus, Setaria and Sorghum; anddicotyledonous species, for example: Abutilon, Amaranthus, Ambrosia,Chenopodium, Chrysanthemum, Conyza, Galium, Ipomoea, Kochia, Nasturtium,Polygonum, Sida, Sinapis, Solanum, Stellaria, Veronica, Viola andXanthium. Weeds can also include plants which may be considered cropplants but which are growing outside a crop area (‘escapes’), or whichgrow from seed left over from a previous planting of a different crop(‘volunteers’). Such volunteers or escapes may be tolerant to certainother herbicides.

Preferably the weeds to be controlled and/or growth-inhibited, includemonocotyledonous weeds, more preferably grassy monocotyledonous weeds,in particular those from the following genus: Agrostis, Alopecurus,Apera, Avena, Brachiaria, Bromus, Cenchrus, Cyperus (a genus of sedges),Digitaria, Echinochloa, Eleusine, Eriochloa, Fimbristylis (a genus ofsedges), Juncus (a genus of rushes), Leptochloa, Lolium, Monochoria,Ottochloa, Panicum, Pennisetum, Phalaris, Poa, Rottboellia, Sagittaria,Scirpus (a genus of sedges), Setaria and/or Sorghum, and/or volunteercorn (volunteer maize) weeds; in particular: Alopecurus myosuroides(ALOMY, English name “blackgrass”), Apera spica-venti, Avena fatua(AVEFA, English name “wild oats”), Avena ludoviciana, Avena sterilis,Avena sativa (English name “oats” (volunteer)), Brachiaria decumbens,Brachiaria plantaginea, Brachiaria platyphylla (BRAPP), Bromus tectorum,Digitaria horizontalis, Digitaria insularis, Digitaria sanguinalis(DIGSA), Echinochloa crus-galli (English name “common barnyard grass”,ECHCG), Echinochloa oryzoides, Echinochloa colona or colonum, Eleusineindica, Eriochloa villosa (English name “woolly cupgrass”), Leptochloachinensis, Leptochloa panicoides, Lolium perenne (LOLPE, English name“perennial ryegrass”), Lolium multiflorum (LOLMU, English name “Italianryegrass”), Lolium persicum (English name “Persian darnel”), Loliumrigidum, Panicum dichotomiflorum (PANDI), Panicum miliaceum (Englishname “wild proso millet”), Phalaris minor, Phalaris paradoxa, Poa annua(POAAN, English name “annual bluegrass”), Scirpus maritimus, Scirpusjuncoides, Setaria viridis (SETVI, English name “green foxtail”),Setaria faberi (SETFA, English name “giant foxtail”), Setaria glauca,Setaria lutescens (English name “yellow foxtail”), Sorghum bicolor,and/or Sorghum halepense (English name “Johnson grass”), and/or Sorghumvulgare; and/or volunteer corn (volunteer maize) weeds.

In one embodiment, grassy monocotyledonous weeds to be controlledcomprise weeds from the genus: Agrostis, Alopecurus, Apera, Avena,Brachiaria, Bromus, Cenchrus, Digitaria, Echinochloa, Eleusine,Eriochloa, Leptochloa, Lolium, Ottochloa, Panicum, Pennisetum, Phalaris,Poa, Rottboellia, Setaria and/or Sorghum, and/or volunteer corn(volunteer maize) weeds; in particular: weeds from the genus Agrostis,Alopecurus, Apera, Avena, Brachiaria, Bromus, Cenchrus, Digitaria,Echinochloa, Eleusine, Eriochloa, Leptochloa, Lolium, Panicum, Phalaris,Poa, Rottboellia, Setaria, and/or Sorghum, and/or volunteer corn(volunteer maize) weeds.

In a further embodiment, the grassy monocotyledonous weeds are“warm-season” (warm climate) grassy weeds; in which case they preferablycomprise (e.g. are): weeds from the genus Brachiaria, Cenchrus,Digitaria, Echinochloa, Eleusine, Eriochloa, Leptochloa, Ottochloa,Panicum, Pennisetum, Phalaris, Rottboellia, Setaria and/or Sorghum,and/or volunteer corn (volunteer maize) weeds. More preferably, thegrassy monocotyledonous weeds, e.g. to be controlled and/orgrowth-inhibited, are “warm-season” (warm climate) grassy weedscomprising (e.g. being): weeds from the genus Brachiaria, Cenchrus,Digitaria, Echinochloa, Eleusine, Eriochloa, Panicum, Setaria and/orSorghum, and/or volunteer corn (volunteer maize) weeds.

In another particular embodiment the grassy monocotyledonous weeds, are“cool-season” (cool climate) grassy weeds; in which case they typicallycomprise weeds from the genus Agrostis, Alopecurus, Apera, Avena,Bromus, Lolium and/or Poa.

Various aspects and embodiments of the present invention will now beillustrated in more detail by way of example. It will be appreciatedthat modification of detail may be made without departing from the scopeof the invention.

PREPARATION EXAMPLES

Throughout the following examples, 1H NMR spectra were recorded at 400MHz or 500 MHz, unless otherwise stated, either on a Varian Unity Inovainstrument or Bruker AVANCE-II instrument.

The following abbreviations are used: s=singlet; d=doublet; dd=doubledoublet; t=triplet, q=quartet; m=multiplet. The term app. is used forapparent and br. denotes a broader signal.

Molecules are given their known names or named according to the namingprograms within Accelrys Draw 4.0 or Symyx Notebook 6.6. If suchprograms are unable to name a molecule, the molecule is named usingagreed naming conventions.

Example 1 Preparation of compound A1 (tert-butylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate) 1.1Preparation of 4-methyl-2-(3-pyridyl)thiazole-5-carboxylate ethyl ester(compound 1.1001)

To a flask charged with thionicotinamide (10 g, 72.3 mmol) was addedethyl-2-chloroacetoacetate (11.9 g, 72.4 mmol) and heated at reflux inethanol (100 mL) overnight. The next morning solvent was removed invacuo and the residue partitioned between EtOAc and sat. aq. NaHCO₃solution. The aqueous phase was extracted with two further portions ofEtOAc. The combined organic extracts were washed with brine then driedover MgSO₄ and concentrated in vacuo. The resulting mixture was purifiedvia flash chromatography on silica gel using an EtOAc/isohexane gradientto give the desired compound(4-methyl-2-(3-pyridyl)thiazole-5-carboxylate ethyl ester, 11.9 g) as apale brown oil which slowly solidified.

1H NMR (400 MHz, CDCl₃) δ=9.17 (1H, m), 8.69 (1H, dd), 8.24 (1H, m),7.40 (1H, m), 4.37 (2H, q), 2.80 (3H, s), 1.40 (3H, t)

1.2 Preparation of 4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid(1.2001)

A solution of 4-methyl-2-(3-pyridyl)thiazole-5-carboxylate ethyl ester(compound 1.1001; 35.2 g, 142 mmol) in methanol (462 mL) was cooled inice/water then a solution of NaOH (17.0 g, 425 mmol) in water (214 mL)was added slowly with stirring and stirred without cooling for one hour.

2M HCl (216 mL) was added slowly with stirring and ice/water cooling.The mixture was stirred for a further 30 mins. The resulting precipitatewas filtered, washed with water and air-dried to give the desiredcompound (4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid, 28.1 g) asan off white solid.

1H NMR (400 MHz, d6-DMSO) δ=13.54 (1H, br. s.), 9.16 (1H, d), 8.72 (1H,dd), 8.35 (1H, m), 7.56 (1H, dd) 2.70 (3H, s)

1.3 Preparation of tert-butylN-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (1.3001)

To a suspension of 4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid(compound 1.2001; 22.4 g, 101.7 mmol) in 2-methylpropan-2-ol (448 mL)and toluene (448 mL) was added Et₃N (14.2 mL, 101 mmol) and the reactionstirred for five minutes at room temperature before DPPA (27.8 g, 101mmol) was added slowly with stirring and cooling to maintain thetemperature below ambient. The reaction was heated gradually to refluxfor 3 hours, then allowed to cool overnight to room temperature.

The solvent was removed in vacuo and the residue purified via flashcolumn chromatography on silica gel using an EtOAc/isohexane gradient togive the desired compound (tert-butylN-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 25.8 g) as a beigesolid.

1H NMR (400 MHz, CDCl₃) δ=9.09 (1H, s), 8.59 (1H, d), 8.16 (1H, dd),7.36 (1H, m), 6.72 (1H, br. s), 2.37 (3H, s), 1.49 (9H, br. s.)

1.4 Preparation of tert-butylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (A1)

A solution of tert-butyl N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate(compound 1.3001; 21.2 g, 72.7 mmol) in anhydrous DMF (245 mL) wascooled in ice/water and NaH 60% w/w (3.49 g, 87.3 mmol) was addedportion-wise with stirring, then warmed to ambient over 5 minutes. Themixture was re-cooled in ice/water and then a solution of MeI (11.35 g,80.0 mmol) in dry DMF (5 mL) was added dropwise with stirring andcooling over 30 minutes. The reaction was stirred at room temperatureovernight and then cautiously quenched with water (1000 mL) and 2M HCl(7.29 mL). The reaction mixture was extracted three times with EtOAc,the combined organic extracts were washed twice with brine then driedover MgSO₄. The solvent was removed in vacuo and the residue purifiedvia flash chromatography on silica gel using an EtOAc/isohexane gradientto give the desired compound (tert-butylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 25.1 g) as abeige solid.

1H NMR (400 MHz, CDCl₃) δ=9.08 (1H, d), 8.63 (1H, dd), 8.17 (1H, d),7.36 (1H, dd), 3.22 (3H, s), 2.33 (3H, s), 1.44 (9H, br.s.)

Example 2 Preparation of tert-butylN-methyl-N-(4-methyl-2-pyrimidin-5-yl-thiazol-5-yl)carbamate (A2)

To a flask charged with pyrimidin-5-ylboronic acid (150.0 mg, 1.21 mmol)was added EtOH (2.7 mL) and toluene (5.3 mL) then 2M aq. K₂CO₃ (1.2 mL,2.4 mmol) was added. The reaction was set stirring and tert-butylN-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (409 mg, 1.33 mmol)was added, followed by Pd(PPh₃)₄ (70 mg, 0.06 mmol). The mixture washeated at 90° C. for two hours and then allowed to cool overnight toambient.

The mixture was diluted with EtOAc and washed twice with brine. Thecombined aqueous washings were back-extracted with EtOAc and thecombined organic extracts were washed with brine and then dried overMgSO₄. The solvent was removed in vacuo and the residue purified viaflash column chromatography on silica gel using an EtOAc/isohexanegradient to afford the desired compound (tert-butylN-methyl-N-(4-methyl-2-pyrimidin-5-yl-thiazol-5-yl)carbamate, 170 mg) asa straw coloured gum.

1H NMR (400 MHz, CDCl₃) δ=9.23 (1H, s), 9.18 (2H, s), 3.23 (3H, s), 2.35(3H, s), 1.45 (9H, br.s.)

Example 3 Preparation of tert-butylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A3)

To a flask charged with tert-butylN-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (8.78 g, 27.8 mmol)and (5-fluoro-3-pyridyl)boronic acid (4.71 g, 33.4 mmol) was addedethanol (55.7 mL) and toluene (111.6 mL). Pd(PPh₃)₄ (1.50 g, 1.30 mmol)was added and the mixture stirred vigorously. 2M aq. K₂CO₃ (25.5 mL,51.0 mmol) was added and the reaction was heated to reflux for 7 hours,then left to cool to ambient overnight.

Solvent was removed in vacuo and the crude material was re-dissolved inCHC1₃ and washed with water. The organic phase was concentrated in vacuoand the residue purified via flash column chromatography on silica gelusing an EtOAc/isohexane gradient to give the desired compound(tert-butylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate,6.92 g) as a beige solid.

1H NMR (400 MHz, CDCl₃) δ=8.85-8.89 (1H, m), 8.49 (1H, d), 7.93 (1H,dd), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br.s).

Example 4 Preparation of tert-butylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (A35) 4.1Preparation of Compound A35

To a flask charged with tert-butylN-(2-bromo-4-methyl-thiazol-5-yl)carbamate (11.31 g, 38.6 mmol) and(5-fluoro-3-pyridyl)boronic acid (6.52 g, 46.3 mmol) was added toluene(151 mL) and ethanol (75 mL). Pd(PPh₃)₄ (2.20 g, 1.90 mmol) was added,followed by 2M aq K₂CO₃ (38.6 mL, 77.2 mmol). The reaction was heated toreflux for five and a half hours. The reaction mixture was cooled toroom temperature and concentrated in vacuo to remove the organics. Themixture was diluted with CHCl₃ and washed with water. The organic phasewas concentrated in vacuo and the residue purified via flash columnchromatography on silica using an EtOAc/isohexane gradient to afford thedesired compound (tert-butylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate, 10.2 g) as abeige solid.

1H NMR (400 MHz, CDCl₃) δ=8.87 (1H, m), 8.44 (1H, d), 7.94-7.87 (1H, m),6.73 (1H, br. s), 2.39 (3H, s), 1.55 (9H, s)

4.2 Alternative preparation of tert-butylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A3)

Compound A35 may also be used as an intermediate in an alternativemethod of producing compound A3.

To a round bottomed flask charged with tert-butylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (800 mg, 2.59mmol) and K₂CO₃ (429 mg, 3.10 mmol) was added iodomethane (807 mg, 5.69mmol) as a solution in MeCN (20 mL) and the mixture set vigorouslystirring. After 5 minutes the reaction was heated to reflux for 2 hours.Upon cooling the mixture was filtered through celite and concentrated invacuo. The resulting semi-solid was purified via flash columnchromatography on silica gel using an EtOAc/isohexane gradient to affordthe desired compound (tert-butylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate, 449mg) as a yellow gum.

1H NMR (400 MHz, CDCl₃) δ=8.85-8.89 (1H, m), 8.49 (1H, d), 7.93 (1H,dd), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br.s.)

Example 5 Preparation of tert-butylN-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carbamate(A16) 5.1 Preparation of tert-butylN-(2-bromo-4-methyl-thiazol-5-yl)carbamate (compound 5.1001)

To a flask charged with 2-bromo-4-methyl-thiazole-5-carboxylic acid (5.0g, 22.5 mmol) and Et₃N (3.14 mL, 22.5 mmol) was added t-BuOH (193 mL)and the mixture was heated to reflux. DPPA (4.89 mL, 22.5 mmol) wasadded dropwise over ca. 15 mins, then stirred at reflux for a further6.5 hours, then allowed to cool overnight.

The reaction mixture was concentrated in vacuo and the residue wasdiluted with EtOAc (95 mL) and washed with water (140 mL). The aqueousphase was back-extracted twice more with EtOAc and the combined organicswere washed with brine and dried over MgSO₄. The solvent was removed invacuo and the residue purified via flash column chromatography on silicagel using an EtOAc/isohexane gradient to afford the desired compound(tert-butyl N-(2-bromo-4-methyl-thiazol-5-yl)carbamate, 5.4 g) as anopaque gum.

1H NMR (400 MHz, CDCl₃) 6.32 (1H, br. s), 2.29 (3H, s), 1.51 (9H, s)

5.2 Preparation of tert-butylN-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (5.2001)

To a flask charged with tert-butylN-(2-bromo-4-methyl-thiazol-5-yl)carbamate (32.0 g, 109.12 mmol) wasadded DMF (130 mL), the reaction was cooled in an ice bath and NaH 60%w/w (4.8 g, 120 mmol) added portion-wise with stirring and cooling tomaintain the temperature in the range 5-10° C. The mixture was stirredfor 10 mins then allowed to warm to ambient over ca. 40 mins. Thereaction was cooled in an ice bath then iodomethane (16.27 g, 114.6mmol) in DMF (100 mL) was added slowly with stirring and cooling tomaintain the temperature in the range 5-10° C. The reaction was allowedto warm to ambient and stirred for a further 5 hours. The reactionmixture was cooled in an ice bath and quenched by the cautious additionof water (920 mL).

The reaction mixture was extracted three times with EtOAc and thecombined organics washed with brine and dried over MgSO₄. The solventwas removed in vacuo and the residue purified via flash columnchromatography on silica gel eluting with an EtOAc/isohexane gradient toafford the desired compound (tert-butylN-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate, 33.2 g) as acolourless oil.

1H NMR (400 MHz, CDCl₃) δ=1.43 (9H, br. s.), 2.24 (3H, s), 3.16 (3H, s)

5.3 Preparation of3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(5.3001)

To a flask charged with 3-bromo-5-(difluoromethoxy)pyridine (4.50 g,20.1 mmol) was added bispinacolatodiboron (7.65 g, 30.1 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]palladium(ii) dichloridedichloromethane adduct (837 mg, 1.00 mmol) and KOAc (6.5 g, 64.0 mmol).1,4-Dioxane (95 mL) was added and the mixture was purged with dry N₂ andheated at 100° C. for 1 hour.

The reaction was cooled to ambient and concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ and filtered through celite. Thefiltrate was concentrated in vacuo to give a thick black oil which waspurified via flash column chromatography on silica gel using anEtOAc/isohexane gradient to afford the desired compound(3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine,3.95 g) as a straw coloured oil which crystallized on standing.

¹1H NMR (400 MHz, CDCl₃) δ=8.80 (1H, d), 8.54 (1H, d), 7.82 (1H, m),6.76-6.36 (1H, t), 1.36 (12H, s)

5.4 Preparation of tert-butylN-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carbamate(A16)

To a microwave vial charged with tert-butylN-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (500 mg, 1.59 mmol)and3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(430 mg, 1.59 mmol) was added EtOH (2 mL) and toluene (4 mL). Pd(PPh₃)₄(85.3 mg, 0.074 mmol) was added, followed by 2M K₂CO₃ (1.45 mL, 2.90mmol) and the tube sealed. The mixture was heated to 130 C for 30minutes under microwave irradiation.

Upon cooling the solvent was removed in vacuo and residue partitionedbetween CHCl₃ and water. The organic phase was concentrated in vacuo togive a black gum which was purified via flash column chromatography onsilica gel using a EtOAc/isohexane gradient to afford impure tert-butylN-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carbamate.This material was further purified via flash column chromatography on aC₁₈ reverse phase column using a water (0.1% formic acid modifier)/MeCN(0.1% formic acid modifier) gradient to afford the desired compound(tert-butylN-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carbamate,352 mg).

1H NMR (400 MHz, CDCl₃) δ=8.91 (1H, d), 8.50 (1H, d), 7.99 (1H, s),6.82-6.41 (1H, t), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br. s)

Example 6 Preparation of ethylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (A19)

To a flask charged with N,4-dimethyl-2-(3-pyridyl)thiazol-5-amine (300.0mg, 1.46 mmol) dissolved in CH₂Cl₂ (4 mL) was added pyridine (173.4 mg,2.192 mmol) and DMAP (17.9 mg, 0.147 mmol). The reaction mixture wascooled in an ice bath and a solution of ethyl chloroformate (206 mg,1.90 mmol) in CH₂Cl₂ (1 mL) was added drop-wise. After one hour atambient the solvent was removed in vacuo. The residue was partitionedbetween water and EtOAc and the organic phase washed once with brinethen dried (MgSO₄). The solvent was removed in vacuo and the residuepurified via flash column chromatography on silica gel using anEtOAc/isohexane gradient as eluent to afford the target compound (ethylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 280 mg) as astraw coloured gum.

1H NMR (400 MHz, CDCl₃) δ=9.08 (1H, d), 8.64 (1H, dd), 8.17 (1H, m),7.37 (1H, dd), 4.20 (2H, q), 3.27 (3H, s), 2.33 (3H, s), 1.24 (3H, app.br. s)

Example 7 Preparation of3-tert-butyl-1-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]urea (A21)7.1 Preparation of 2-(5-fluoro-3-pyridyl)-N,4-dimethyl-thiazol-5-aminehydrochloride (7.1001)

To a solution of tert-butylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate(4.23 g, 13.1 mmol) in CH₂Cl₂ (66 mL), cooled with an ice bath, wasadded 2M hydrogen chloride in Et₂O (65.4 mL, 130.7 mmol) slowly withstirring. The mixture was stirred in the ice bath for a further 5minutes then allowed to stand overnight and stirred at ambient for afurther 2 days.

Concentration in vacuo yielded the desired compound(2-(5-fluoro-3-pyridyl)-N,4-dimethyl-thiazol-5-amine hydrochloride, 3.84g) as an orange solid.

1H NMR (400 MHz, d6-DMSO) δ=8.79 (1H, m), 8.51 (1H, d), 8.01 (1H, m),2.85 (3H, s), 2.25 (3H, s)

7.2 Preparation of3-tert-butyl-1-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]urea (A21)

A solution of N,4-dimethyl-2-(3-pyridyl)thiazol-5-amine hydrochloride(600.0 mg, 2.92 mmol) in CH₂Cl₂ (9 mL) was cooled in an ice bath and asolution of t-butylisocyanate (348 mg, 3.51 mmol) in CH₂Cl₂ (1 mL) wasadded drop-wise. The reaction was allowed to warm to ambient and allowedto stir for 3 days.

The solvent was removed in vacuo and the residue purified via flashcolumn chromatography on silica gel eluted with a CH₂Cl₂/EtOAc gradientto afford the desired compound(3-tert-butyl-1-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]urea, 300mg) as a white solid.

1H NMR (400 MHz, CDCl₃) δ=9.12 (1H, d), 8.67 (1H, dd), 8.19 (1H, m),7.39 (1H, dd), 4.48 (1H, br. s), 3.20 (3H, s), 2.35 (3H, s), 1.30 (9H,br. s)

Example 8 Preparation of S-tert-butylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamothioate (A22)

To a flask charged with N,4-dimethyl-2-(3-pyridyl)thiazol-5-aminehydrochloride (300.0 mg, 1.46 mmol) was added CH₂Cl₂ (4 mL), pyridine(173.4 mg, 2.19 mmol) and DMAP (17.9 mg, 0.15 mmol). The reactionmixture was cooled in an ice bath and a solution of S-tert-butylchlorothioformate (290 mg, 1.90 mmol) in CH₂Cl₂ (1 mL) was addeddrop-wise. The reaction was allowed to stir at ambient for one hour.

The solvent was removed in vacuo and the residue partitioned betweenwater and EtOAc. The organic phase was washed with brine then dried(MgSO₄). Concentration in vacuo afforded a thick residue which waspurified via flash column chromatography on silica gel using anEtOAc/isohexane gradient to afford the desired compound (S-tert-butylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamothioate, 290 mg)as a pale yellow gum.

1H NMR (400 MHz, CDCl₃) δ=9.12 (1H, d), 8.66 (1H, dd), 8.20 (1H, m),7.38 (1H, dd), 3.25 (3H, s), 2.35 (3H, s), 1.47 (9H, m)

Example 9 Preparation of tert-butylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamodithioate (A23)

To a flask charged with N,4-dimethyl-2-(3-pyridyl)thiazol-5-aminehydrochloride (300.0 mg, 1.47 mmol) was added EtOH (1.0 mL). The mixturewas cooled in an ice bath and carbon disulphide (127 μL, 2.11 mmol) wasadded followed by K₂CO₃ (235 mg, 1.68 mmol). The mixture was allowed towarm gradually to ambient overnight.

2-Iodo-2-methyl-propane (194 μL, 1.47 mmol) was added and the reactionstirred at ambient for three days. The solvent was removed in vacuo andthe residue was partitioned between water and EtOAc. The organic phasewas washed once with brine and concentrated in vacuo and the residuepurified via flash column chromatography on silica gel using anEtOAc/isohexane gradient to afford the desired compound (tert-butylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamodithioate, 37 mg)as a pale yellow gum.

1H NMR (400 MHz, CDCl₃) δ=9.14 (1H, d), 8.68 (1H, dd), 8.25 (1H, m),7.44 (1H, m), 3.65 (3H, s), 2.32 (3H, s), 1.59 (9H, s)

Example 10 Preparation of tert-butylN-[2-(5-methoxy-3-pyridyl)-4-(trifluoromethyl)thiazol-5-yl]-N-methyl-carbamate(A28)

To a microwave tube charged with tert-butylN-[2-bromo-4-(trifluoromethyl)thiazol-5-yl]-N-methyl-carbamate (200 mg,0.55 mmol) and3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (131mg, 0.56 mmol) was added ethanol (1.2 mL) and toluene (2.4 mL) then 2MK₂CO₃ (549 μL, 1.1 mmol) followed by Pd(PPh₃)₄ (33 mg, 0.03 mmol). Thetube was sealed and the reaction was heated to 130° C. for 20 mins undermicrowave irradiation.

Upon cooling the solvent was removed in vacuo and the residue dissolvedin CHCl₃, and washed with water. The reaction mixture was concentratedin vacuo to leave a dark brown gum, which was purified via flash columnchromatography on silica gel using an EtOAc/isohexane gradient to affordthe desired compound (tert-butylN-[2-(5-methoxy-3-pyridyl)-4-(trifluoromethyl)thiazol-5-yl]-N-methyl-carbamate,92 mg) as a beige solid.

1H NMR (500 MHz, CDCl₃) δ=8.64 (1H, d), 8.40 (1H, d), 7.77 (1H, br. s),3.95 (3H, s), 3.26 (3H, s), 1.43 (9H, br. s)

Example 11 Preparation of of tert-butylN-[4-bromo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A30)

To a flask charged with tert-butylN-methyl-N-[2-(3-pyridyl)thiazol-5-yl]carbamate (150 mg, 0.52 mmol) wasadded MeCN (3.0 mL), the mixture was purged with dry N₂ then NBS (183mg, 1.03 mmol) was added in a single portion. The mixture was stirredfor an hour at ambient and then left to stand for 4 days.

The reaction mixture was concentrated in vacuo and the residue purifiedvia flash column chromatography on silica gel eluting with aEtOAc/isohexane gradient to afford the desired compound (tert-butylN-[4-bromo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 110 mg) ascolourless gum.

1H NMR (400 MHz, CDCl₃) δ=9.08 (1H, d), 8.70-8.64 (1H, m), 8.20 (1H, m),7.42-7.37 (1H, m), 3.25 (3H, s), 1.46 (9H, br. s)

Example 12 Preparation of tert-butylN-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A31)

To a flask charged with tert-butylN-methyl-N-[2-(3-pyridyl)thiazol-5-yl]carbamate (1.1 g, 3.8 mmol) wasadded MeCN (33 mL), the reaction was cooled in ice, purged with dry N₂then NIS (1.78 g, 7.91 mmol) was added in a single portion. The mixturewas allowed to warm to ambient and stirred for a further 7 days.

The reaction mixture was concentrated in vacuo and the residue purifiedvia flash column chromatography on silica gel eluting with aEtOAc/isohexane gradient to afford the desired compound (tert-butylN-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 1.02 g) as abeige solid.

1H NMR (400 MHz, CDCl₃) δ=9.08 (1H, d), 8.67 (1H, dd), 8.22 (1H, m),7.40 (1H, dd), 3.24 (3H, s), 1.46 (9H, br. s)

Example 13 Preparation of tert-butylN-[4-fluoro-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A32)

To a flask charged with tert-butylN-methyl-N-[2-(3-pyridyl)thiazol-5-yl]carbamate (150 mg, 0.51 mmol),dissolved in MeCN (6.1 mL) and purged with dry N₂ was added SelectFluor®(364.7 mg, 1.03 mmol) in a single portion. The reaction was againflushed with dry N₂ then stirred ambientfor 5 hours. Water (15 mL) addedthen the mixture was extracted three times with EtOAc. The combinedorganics were dried (MgSO₄) and the solvent was concentrated in vacuo.The residue was purified via flash column chromatography on silica geleluting with an EtOAc/isohexane gradient to afford the desired compound(tert-butyl N-[4-fluoro-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate,60 mg) as a straw coloured gum.

1H NMR (500 MHz, CDCl₃) δ=9.06 (1H, d), 8.65 (1H, d), 8.13 (1H, d), 7.38(1H, dd), 3.30 (3H, br. s), 1.50 (9H, br. s)

Example 14 Preparation of3-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]imidazolidine-2,4-dione(A33) 14.1 Preparation of 4-methyl-2-(3-pyridyl)thiazole (14.1001)

To a flask charged with thionicotinamide (50 g, 361.8 mmol) was addedEtOH (300 mL) followed by chloroacetone (40 g, 432.3 mmol) and themixture was heated to reflux overnight.

Upon cooling the solvent was removed in vacuo and the residue wasdissolved in water (400 mL) and made basic with NaHCO₃. This mixture wasextracted three times with EtOAc and the combined organics washed oncewith brine then dried (MgSO₄). The organics were concentrated in vacuoand the residue purified via flash column chromatography on silica gelusing an EtOAc/isohexane gradient to give the desired compound(4-methyl-2-(3-pyridyl)thiazole, 38.8 g) as a straw coloured oil.

1H NMR (400 MHz, CDCl₃) δ=9.15 (1H, d), 8.63 (1H, dd), 8.22 (1H, m),7.36 (1H, m), 6.95 (1H, s), 2.53 (3H, s)

14.2 Preparation of 5-bromo-4-methyl-2-(3-pyridyl)thiazole (14.2001)

4-Methyl-2-(3-pyridyl)thiazole (10.0 g, 56.7 mmol) was dissolved in DMF(100 mL) and NBS (11.1 g, 62.4 mmol) was added with cooling to keep thetemperature at below ambient. The reaction was heated at 50 C for ca. 3hours and left to cool overnight.

The reaction was quenched with water (400 mL) and extracted three timeswith EtOAc. The combined organics were washed three times with brine anddried (MgSO₄).

The reaction mixture was concentrated in vacuo and the residue waspurified via flash column chromatography on silica gel using anEtOAc/isohexane gradient to give 5-bromo-4-methyl-2-(3-pyridyl)thiazole(13.24 g, 51.9 mmol) as a beige solid.

1H NMR (400 MHz, CDCl₃) δ=9.06 (1H, m) 8.66 (1H, dd) 8.15 (1H, s)7.35-7.41 (1H, m) 2.48 (3H, s)

14.3 Preparation of3-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]imidazolidine-2,4-dione(A33)

To a microwave tube charged with 5-bromo-4-methyl-2-(3-pyridyl)thiazole(136 mg, 0.53 mmol) was added 3-methylimidazolidine-2,4-dione (121.6 mg,1.07 mmol) and N,N′-dimethylethylenediamine (4.7 mg, 0.05 mmol)dissolved in 1,4-dioxane (3.2 mL). CuI (10.2 mg, 0.05 mmol) and K₂CO₃(295 mg, 2.13 mmol) were added, the tube was sealed the mixture washeated at 160° C. for 1 hour under microwave irradiation.

The solvent was removed in vacuo and the residue partitioned betweenwater and EtOAc, filtered to remove residual solid and partitioned. Theaqueous phase was extracted with two further portions of EtOAc. Thecombined organic extracts were washed with brine, dried (MgSO₄), andconcentrated in vacuo. The residue was purified via reverse phase flashchromatography a C₁₈ column eluted with a water and MeCN gradient togive the desired compound(3-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]imidazolidine-2,4-dione,21 mg) as a white solid.

1H NMR (400 MHz, CDCl₃) δ=9.08 (1H, d), 8.66 (1H, dd), 8.17 (1H, m),7.39 (1H, m), 4.28 (2H, s), 3.15 (3H, s), 2.43 (3H, s)

Example 15 Preparation of3-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]oxazolidin-2-one (A38)15.1 Preparation of 2-chloroethylN-tert-butoxycarbonyl-N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate(16.1001)

To a flask charged with tert-butylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (800 mg, 2.59mmol) was added dry THF (7 mL). The reaction was cooled in ice thensodium hydride 60% w/w (114 mg, 2.85 mmol) was added portionwise withstirring over 10 mins during which time the reaction had set solid.After standing at ambient for 20 mins, a solution of chloroethylchloroformate (407 mg, 2.85 mmol) in THF (0.3 mL) was added. After afurther 10 minutes stirring a hazy solution resulted, which was stirredfor a further 3 hours at ambient.

The reaction was quenched with water (1 mL) and 2M HCl (528 μl) and thenconcentrated in vacuo, redissolved in CH₃Cl and partitioned with water.The organic solvent was concentrated in vacuo to yield a pale orange gumwhich was purified via flash column chromatography on silica gel usingan EtOAc/isohexane gradient to give the desired compound (2-chloroethylN-tert-butoxycarbonyl-N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate,520 mg) as a colourless gum.

1H NMR (400 MHz, CDCl₃) δ=8.90 (1H, m), 8.52 (1H, d), 7.96 (1H, m), 4.46(2H, m), 3.68 (2H, m), 2.33 (3H, s), 1.48 (9H, s)

15.2 Preparation of 2-chloroethylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (16.2001)

A flask charged with 2-chloroethylN-tert-butoxycarbonyl-N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate(625 mg, 1.50 mmol) and CH₂Cl₂ (6 mL) was cooled in an ice bath and TFA(3 mL) was added slowly with stirring for 5 minutes then left at ambientfor 1 hour 45 minutes.

The solvent was removed in vacuo to leave a gum which was dissolved inCHCl₃, shaken with water and passed through a hydrophobic phaseseparating cartridge. The aqueous phase was neutralised with sat. aq.NaHCO₃, extracted with CHCl₃ and passed through a hydrophobic phaseseparating cartridge. The combined organics were concentrated in vacuoto give the desired compound (2-chloroethylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate, 393 mg).

1H NMR (400 MHz, CDCl₃) δ=8.88 (1H, m), 8.47 (1H, d), 7.94 (1H, m), 6.93(1H, br. s), 4.50 (2H, m), 3.77 (2H, m), 2.41 (3H, s)

15.3 Preparation of3-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]oxazolidin-2-one (A38)

A flask charged with 2-chloroethylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (202 mg, 0.64mmol) and DMF (1.45 mL) was cooled in a salt/ice bath then sodiumhydride 60% w/w (30.7 mg, 0.768 mmol) was added in one portion. Thereaction mixture was stirred with cooling for 20 minutes then at ambientfor a further 3 hours.

The reaction was cooled in ice then quenched with water (5.8 mL) and 2MHCl (63 μL). The reaction mixture was extracted three times with EtOAcand the combined organics washed once with brine and dried (MgSO₄), thenconcentrated in vacuo. The residue was purified via columnchromatography on silica gel using an EtOAc/isohexane gradient to affordthe desired compound(3-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]oxazolidin-2-one, 120mg).

1H NMR (400 MHz, CDCl₃) δ=8.87 (1H, m), 8.51 (1H, d), 7.96-7.90 (1H, m),4.64-4.53 (2H, m), 4.06-3.97 (2H, m), 2.52 (3H, s)

Example 16 Preparation of methyl5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylate(A39)

To a flask charged with a solution of tert-butylN-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (0.19 g, 0.44mmol) in THF (1 mL) cooled to −78° C. was added n-BuLi (1.6M) in hexanes(0.55 mL, 0.89 mmol) drop-wise over 5 min. After 30 min stirring at −78°C., methyl chloroformate (0.07 mL, 0.89 mmol) was added. The mixture wasstirred at −78° C. for one hour before being allowed to warm to ambient.

The reaction was quenched at room temperature by the addition of sat.aq. NH₄Cl solution and extracted with three portions of CH₂Cl₂. Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuo.The residue was purified via flash column chromatography on silica geleluted with an EtOAc/isohexane gradient, followed by furtherpurification with reverse phase HPLC to give the desired compound(methyl5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylate,4.7 mg).

1H NMR (400 MHz, CDCl₃) δ=9.23 (1H, br. s), 8.80 (1H, d), 8.64 (1H, d),7.74 (1H, dd), 3.98 (3H, s), 3.31 (3H, s), 1.65-1.32 (9H, br. s)

Example 17 Preparation of tert-butylN-methyl-N-[2-(3-pyridyl)-4-vinyl-thiazol-5-yl]carbamate (A40)

To a microwave tube charged with tert-butylN-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (80 mg, 0.19mmol), tributyl(vinyl)stannane (0.122 g, 0.38 mmol) and PdCl₂(PPh₃)₂(0.14 mg, 0.02 mmol) was added 1,4-dioxane (1 mL). The tube was sealedand heated at 140° C. for 30 min under microwave irradiation.

The reaction mixture was concentrated in vacuo and the residue purifiedvia flash column chromatography on silica gel eluting with anEtOAc/isohexane gradient to give the desired compound (tert-butylN-methyl-N-[2-(3-pyridyl)-4-vinyl-thiazol-5-yl]carbamate, 41.4 mg) as abrown gum.

1H NMR (400 MHz, CDCl₃) δ=9.08-9.01 (1H, m), 8.58 (1H, dd), 8.16 (1H,dd), 7.31 (1H, m), 6.50 (1H, dd), 6.16 (1H, dd), 5.42 (1H, dd), 3.17(3H, s), 1.36 (9H, br. s)

Example 18 Preparation of tert-butylN-[4-ethynyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A41)

To a microwave tube charged with tert-butylN-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (100 mg, 0.24mmol), tributyl(ethynyl)stannane (150 mg, 0.45 mmol) and PdCl₂(PPh₃)₂(17 mg, 0.024 mmol) was added 1,4-dioxane (2 mL) and the tube wassealed. The reaction was sealed and heated to 140° C. for 30 min undermicrowave irradiation.

The reaction mixture was concentrated in vacuo and the residue purifiedvia flash column chromatography on silica gel eluting with anEtOAc/isohexane gradient to afford the desired compound (tert-butylN-[4-ethynyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 37 mg) as abrown gum.

1H NMR (400 MHz, CDCl₃) δ=9.09 (1H, d), 8.66 (1H, dd), 8.22 (1H, m),7.38 (1H, dd), 3.43 (3H, s), 1.81 (1H, s), 1.51 (9H, br. s)

Example 19 Preparation of tert-butylN-[4-cyclopropyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A43)

To a microwave tube charged with tert-butylN-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (100 mg, 0.24mmol), cyclopropylboronic acid (27 mg, 0.31 mmol),tricyclohexylphosphine (6.7 mg, 0.024 mmol) and K₃PO₄ (180 mg, 0.84mmol) was added toluene (0.72 mL) and water (50 μL). The solution wasdegassed by vacuum and purged with Ar, Pd(OAc)₂ (2.6 mg, 0.012 mmol) wasadded and the reaction was sealed and heated to 120° C. for 35 min undermicrowave irradiation.

The reaction mixture was then diluted with water and extracted withthree portions of CH₂Cl₂. The combined organics were dried (MgSO₄) andconcentrated in vacuo to give a brown gum which was purified viapreparative reverse phase HPLC to afford the desired compound(tert-butylN-[4-cyclopropyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 1.6 mg).

1H NMR (400 MHz, CDCl₃) δ=9.01 (1H, s), 8.60 (1H, d), 8.14 (1H, m), 7.32(1H, dd), 3.20 (3H, s), 1.89-1.63 (5H, m), 1.39 (9H, br. s)

Example 20 Preparation of5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylicacid (A44)

To a flask charged with tert-butylN-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (0.1 g, 0.24mmol) was added THF (1 mL, 12.3 mmol) and the reaction cooled to −78° C.n-Butyllithium (1.6M) in hexanes (0.30 mL, 0.48 mmol) was then addeddropwise over the course of 5 min. After 30 min stirring at −78° C.,carbon dioxide was bubbled through the reaction mixture for 10 minutesfrom subliming dry ice. The reaction was allowed to warm to roomtemperature then quenched by the addition of sat. aqueous NH₄Cl and theresulting mixture was extracted with three portions CH₂Cl₂. The combinedorganic phases were dried over MgSO₄ and concentrated in vacuo to give abrown gum which was purified via reverse phase HPLC to give the desiredcompound(5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylicacid, 5.9 mg).

1H NMR (400 MHz, CDCl₃) δ=9.37 (1H, app. br. s), 8.78 (1H, app. br.s),8.43 (1H, d), 7.68 (1H, app. br. s), 3.37 (3H, s), 1.46 (9H, br.s)

Example 21 Preparation of3-tert-butoxy-1-methyl-1-(4-methyl-2-(3-pyridyl)thiazol-5-yl)urea (A45)

To a flask charged with tert-butylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (93mg, 0.45 mmol) dissolved in DMF (2 mL) was added K₂CO₃ (82.0 mg, 0.59mmol) and the reaction mixture was cooled to ca. 10° C. Then(tert-butoxycarbonylamino)-4-methylbenzenesulfonate (prepared accordingto the procedure of Thambidurai et al., Synlett 2011, 1993) (156.2 mg,0.54 mmol) was added The resulting orange reaction was stirred for 3days at ambient.

The solvent was removed in vacuo and the residue was dissolved in EtOAc,washed with water and the aqueous phase back-extracted three times withEtOAc. The combined organics were dried (Na₂SO₄), concentrated in vacuoand the residue purified via flash column chromatography on silica geleluting with a CH₂Cl₂/methanol gradient to afford the desired compound(3-tert-butoxy-1-methyl-1-(4-methyl-2-(3-pyridyl)thiazol-5-yl)urea, 93mg) as an orange solid.

1H NMR (400 MHz, CDCl₃) δ=9.12 (1H, s), 8.58 (1H, d), 8.18 (1H, d), 7.43(1H, dd), 6.96 (1H, br. s), 3.28 (3H, s), 2.41 (3H, s), 1.23 (9H, s)

Example 22 Preparation of (4-nitrophenyl)N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (A61)

N,4-Dimethyl-2-(3-pyridyl)thiazol-5-amine (5.19 g, 23.0 mmol) andpyridine (2.73 g, 34.5 mmol) plus DMAP (287 mg, 2.30 mmol) weredissolved in CH₂Cl₂ (75 mL), cooled in an ice bath and a solution of(4-nitrophenyl) chloroformate (6.03 g, 29.9 mmol) in CH₂Cl₂ (25 mL) wasadded drop-wise with stirring. The flask was allowed to warm to ambientand stirred for a further 2 days. The reaction mixture was concentratedin vacuo and the residue partitioned between water and EtOAc. Theaqueous phase was back extracted with EtOAc. The combined organicextracts were combined, washed once with brine, dried over MgSO₄,filtered and the filtrate concentrated in vacuo. The residue waspurified via flash column chromatography on silica gel and eluted with aCH₂Cl₂/EtOAc gradient to afford the desired compound((4-nitrophenyl)-N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate,7.51 g, ca. 92% purity) as a beige solid.

1H NMR (400 MHz, CDCl₃) δ=9.14 (1H, s), 8.67 (1H, dd), 8.33-8.26 (3H,m), 7.39 (1H, dd), 7.23-2.33 (2H, m), 3.40 (3H, s), 2.46 (3H, s)

Example 23 Preparation of 1,1-dimethylprop-2-ynylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (B3)

To a flask charged with 2-methylbut-3-yn-2-ol (84 mg, 1.00 mmol)dissolved in N,N-dimethylformamide (1.5 mL) and cooled in ice was addedsodium hydride (60% suspension in oil w/w) (44 mg, 1.10 mmol). The flaskwas removed from the ice bath and stirred for 15 mins then re-cooled inice/water. (4-Nitrophenyl)N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (200 mg, 0.497mmol) was added with stirring and cooling. The reaction was warmed toroom temperature and stirred for one further hour. The reaction wasquenched with water (6 mL), extracted three times with EtOAc and theorganic extracts washed with brine. The combined organics extracts weredried over MgSO₄ and solvent removed in vacuo. The crude residue waspurified via reverse phase flash chromatography using a C₁₈ silicacolumn and a water/acetonitrile gradient to afford the desired compound(1,1-dimethylprop-2-ynylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 81 mg).

1H NMR (400 MHz, CDCl₃) δ=9.09 (1H, d), 8.64 (1H, dd), 8.18 (1H, d),7.37 (1H, dd), 3.27 (3H, s), 2.59 (1H, s), 2.5 (3H, s), 1.81-1.53 (6H,br. s)

Example 24 Preparation of 1-methylprop-2-ynylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (B2)

To a flask charged with but-3-yn-2-ol (70 mg, 1.00 mmol) dissolved inN,N-dimethylformamide (1.5 mL) and cooled in ice was added sodiumhydride (60% suspension in oil w/w) (44 mg, 1.10 mmol). The flask wasremoved from the ice bath and stirred for 15 mins, then re-cooled withan ice bath. (4-Nitrophenyl)N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (200 mg, 0.50mmol) was added with stirring and cooling. The reaction was warmed toroom temperature and stirred for one further hour.

The reaction was quenched with water (6 mL) and extracted three timeswith EtOAc then the organic extracts washed with brine. The combinedorganic extracts were dried over MgSO₄ and solvent removed in vacuo. Thecrude residue was purified via reverse phase flash chromatography usinga C₁₈ silica column and a water/acetonitrile gradient to afford thedesired compound (1-methylprop-2-ynylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 96 mg) as astraw coloured gum.

1H NMR (400 MHz, CDCl₃) δ=9.09 (1H, d), 8.65 (1H, dd), 8.18 (1H, d),7.38 (1H, dd), 5.43 (1H, br.s), 3.30 (3H, s), 2.51 (1H, br. s), 2.35(3H, s), 1.45 (3H, br. s)

Example 25 Preparation of prop-2-ynylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (B1)

To a flask charged with propargyl alcohol (55.7 mg, 1.00 mmol) dissolvedin N,N-dimethylformamide (1.5 mL), and cooled in ice was added sodiumhydride (60% suspension in oil w/w) (44 mg, 1.10 mmol). The flask wasremoved from the ice bath and stirred for 15 mins, then re-cooled withan ice bath. (4-Nitrophenyl)N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (200 mg, 0.50mmol) was added with stirring and cooling. The reaction was warmed toroom temperature and stirred for one further hour.

The reaction was quenched with water (6 mL) and extracted three timeswith EtOAc then the organic extracts washed once with brine. Thecombined organic extracts were dried over MgSO₄, filtered and solventremoved in vacuo. The crude residue was purified via reverse phase flashchromatography using a C₁₈ silica column and a water/acetonitrilegradient to afford the desired compound (prop-2-ynylN-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 78 mg) as astraw coloured gum.

1H NMR (400 MHz, CDCl₃) δ=9.08 (1H, d), 8.65 (1H, dd), 8.18 (1H, m),7.38 (1H, dd), 4.72 (2H, br. s), 3.31 (3H, s), 2.51 (1H, br. s), 2.35(3H, s)

Example 26 Preparation of tert-butyl N-[2-(5-fluoro-3-pyridylN-oxide)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A62)

To a flask charged with tert-butylN-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A3)(250 mg, 0.77 mmol) was added CH₂Cl₂ (25 mL) and the mixture stirredvigorously at 0° C. (ice bath). mCPBA (382 mg, 1.55 mmol) was added as asingle portion and mixture was allowed to warm to ambient and leftstirring overnight.

The reaction mixture was quenched by the addition of sodiummetabisulfite solution (10% w/w, 100 mL) and the phases separated. Theorganic phase was tested for peroxide (Quantofix® Peroxide 100 teststrips, manufactured by Machery-Nagel) and found to be free of residualperoxide.

The reaction mixture was concentrated in vacuo and the residue purifiedvia flash column chromatography on silica gel eluting with anEtOAc/isohexane gradient to give the desired compound (tert-butylN-[2-(5-fluoro-3-pyridylN-oxide)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A62), 14 mg) as acolourless glass

1H NMR (400 MHz, CDCl₃) δ=8.55 (1H, s), 8.12 (1H, d), 7.54 (1H, dd),3.21 (3H, s), 2.32 (3H, s), 1.46 (9H, br. s)

Tables 3 and 4 below shows compound of formula (I) as made using themethods described above, or in analogous manner to the compoundsdescribed in Examples 1 to 25.

TABLE 3 Compounds of formula (I) Physical Data (¹H NMR, 400 MHz, CDCl₃unless Compound Structure stated) A1

9.08 (1H, d), 8.63 (1H, dd), 8.17 (1H, d), 7.36 (1H, dd), 3.22 (3H, s),2.33 (3H, s), 1.44 (9H, br.s.) A2

9.23 (1H, s), 9.18 (2H, s), 3.23 (3H, s), 2.35 (3H, s), 1.45 (9H, br.s.)A3

8.85-8.89 (1H, m), 8.49 (1H, d), 7.93 (1H, dd), 3.23 (3H, s), 2.33 (3H,s), 1.45 (9H, br.s.) A4

8.92 (1H, d), 8.58 (1H, d), 8.20 (1H, t), 3.23 (3H, s), 2.33 (3H, s),1.45 (9H, br.s.) A5

10.2 (1H, s), 9.32 (1H, s), 9.08 (1H, s), 8.58 (1H, s), 3.21 (3H, s),2.35 (3H, s), 1.44 (9H, br. s) A6

8.62 (1H, d), 8.33 (1H, d), 7.71 (1H, br. s), 3.92 (3H, s), 3.21 (3H,s), 2.32 (3H, s), 1.47 (9H, br. s) A7

9.23 (1H, d), 8.87 (1H, d), 8.47 (1H, dd), 3.24 (3H, s), 2.34 (3H, s),1.45 (9H, br. s) A8

(500 MHz, CDCl₃) 9.19 (1H, s), 9.07 (1H, s), 8.59 (1H, s), 6.76 (1H, br.s), 6.42 (1H, br. s), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br. s) A9

(500 MHz, CDCl₃) 9.31 (1H, d), 9.14 (1H, d), 8.69 (1H, m), 3.24 (3H, s),3.18 (3H, s), 2.35 (3H, s), 1.46 (9H,br. s) A10

(500 MHz, CDCl₃) 9.23 (1H, d), 8.89 (1H, d), 8.44 (1H, s), 3.25 (3H, m),2.36 (3H, s), 1.46 (9H, br. s) A11

(500 MHz, CDCl₃) 8.42 (1H, d), 8.09 (1H, d), 7.49 (1H, s), 4.04 (2H, br.s), 3.21 (3H, s), 2.31 (3H, s), 1.44 (9H, br. s) A12

(500 MHz, CDCl₃) 8.79 (1H, d), 8.50 (1H, m), 8.05 (1H, m), 3.23 (3H, s),2.57 (3H, s), 2.33 (3H, s), 1.59-1.32 (9H, br. s) A13

(500 MHz, CDCl₃) 8.38 (1H, d), 8.15 (1H, d), 7.46 (1H, m), 3.22 (3H, s),3.05 (6H, 2x s), 2.32 (3H, s), 1.44 (9H, br. s) A14

8.66 (1H, d), 8.40 (1H, d), 7.80 (1H, dd), 7.48-7.33 (5H, m), 5.18 (2H,s), 3.22 (3H, s), 2.32 (3H, s), 1.44 (9H, br. s) A15

(400 MHz, DMSO-d6) 10.33 (1H, br. s), 8.50 (1H, d), 8.20 (1H, d),7.60-7.53 (1H, m), 3.15 (3H, s), 2.24 (3H, s), 1.39 (9H, s) A16

8.91 (1H, d), 8.50 (1H, d), 7.99 (1H, s), 6.82-6.41 (1H, t), 3.23 (3H,s), 2.33 (3H, s), 1.45 (9H, br. s) A17

9.18 (1H, d), 8.62 (1H, dd), 8.17 (1H, m), 7.38 (1H, m), 3.63 (2H, q),2.32 (3H, s), 1.43 (9H, br. s), 1.18 (3H, t) A18

9.08 (1H, d), 8.64 (1H, dd), 8.17 (1H, dt), 7.37 (1H, m), 3.74 (3H, br.s), 3.28 (3H, s), 2.33 (3H, s) A19

9.08 (1H, d), 8.64 (1H, dd), 8.17 (1H, m), 7.37 (1H, dd), 4.20 (2H, q),3.27 (3H, s), 2.33 (3H, s), 1.24 (3H, app. br. s) A20

9.09 (1H, d), 8.64 (1H, dd), 8.18 (1H, m), 7.37 (1H, dd), 4.98 (1H, m),3.26 (3H, s), 2.33 (3H, s), 1.23 (6H, br. d) A21

9.12 (1H, d), 8.67 (1H, dd), 8.19 (1H, m), 7.39 (1H, dd), 4.48 (1H, br.s), 3.20 (3H, s), 2.35 (3H, s), 1.30 (9H, br. s) A22

9.12 (1H, d), 8.66 (1H, dd), 8.20 (1H, m), 7.38 (1H, dd), 3.25 (3H, s),2.35 (3H, s), 1.47 (9H, m) A23

9.14 (1H, d), 8.68 (1H, dd), 8.25 (1H, m), 7.44 (1H, m), 3.65 (3H, s),2.32 (3H, s), 1.59 (9H, s) A24

8.89 (1H, s), 8.57 (1H, d), 8.02 (1H, m), 3.27 (3H, s), 1.44 (9H, br. s)A25

9.10 (1H, d), 8.71 (1H, dd), 8.25 (1H, d), 7.42 (1H, dd), 3.27 (3H, s),1.44 (9H, br. s) A26

(500 MHz, CDCl₃) 9.31 (1H, s), 9.23 (2H, s), 3.28 (3H, s), 1.44 (9H, br.s) A27

(500 MHz, CDCl₃) 8.94 (1H, d), 8.66 (1H, d), 8.28 (1H, t), 3.27 (3H, s),1.57-1.33 (9H, br. s) A28

(500 MHz, CDCl₃) 8.64 (1H, d), 8.40 (1H, d), 7.77 (1H, br. s), 3.95 (3H,s), 3.26 (3H, s), 1.43 (9H, br. s) A29

(300 MHz, CDCl₃) 9.08 (1H, s), 8.67 (1H, d), 8.22-8.16 (1H, m), 7.39(1H, dd), 3.26 (3H, s), 1.46 (9H, s) A30

9.08 (1H, d), 8.70-8.64 (1H, m), 8.20 (1H, m), 7.42- 7.37 (1H, m), 3.25(3H, s), 1.46 (9H, br. s) A31

9.08 (1H, d), 8.67 (1H, dd), 8.22 (1H, m), 7.40 (1H, dd), 3.24 (3H, s),1.46 (9H, br. s) A32

(500 MHz, CDCl₃) 9.06 (1H, d), 8.65 (1H, d), 8.13 (1H, d), 7.38 (1H,dd), 3.30 (3H, br. s), 1.50 (9H, br. s) A33

9.08 (1H, d), 8.66 (1H, dd), 8.17 (1H, m), 7.39 (1H, m), 4.28 (2H, s),3.15 (3H, s), 2.43 (3H, s) A34

9.07 (1H, d), 8.62 (1H, dd), 8.15 (1H, m), 7.35 (1H, m), 3.77 (2H, m),3.54 (2H, m), 2.91 (3H, s), 2.42 (3H, s) A35

8.87 (1H, m), 8.44 (1H, d), 7.94-7.87 (1H, m), 6.73 (1H, br. s), 2.39(3H, s), 1.55 (9H, s) A38

8.87 (1H, m), 8.51 (1H, d), 7.96-7.90 (1H, m), 4.64- 4.53 (2H, m),4.06-3.97 (2H, m), 2.52 (3H, s) A39

9.23 (1H, br. s), 8.80 (1H, d), 8.64 (1H, d), 7.74 (1H, dd), 3.98 (3H,s), 3.31 (3H, s), 1.65-1.32 (9H, br. s) A40

9.08-9.01 (1H, m), 8.58 (1H, dd), 8.16 (1H, dd), 7.31 (1H, m), 6.50 (1H,dd), 6.16 (1H, dd), 5.42 (1H, dd), 3.17 (3H, s), 1.36 (9H, br. s) A41

9.09 (1H, d), 8.66 (1H, dd), 8.22 (1H, m), 7.38 (1H, dd), 3.43 (3H, s),1.81 (1H, s), 1.51 (9H, br. s) A43

9.01 (1H, s), 8.60 (1H, d), 8.14 (1H, m), 7.32 (1H, dd), 3.20 (3H, s),1.89-1.63 (5H, m), 1.39 (9H, br. s) A44

9.37 (1H, app. br. s), 8.78 (1H, app. br. s), 8.43 (1H, d), 7.68 (1H,app. br. s), 3.37 (3H, s), 1.46 (9H, br. s) A45

9.12 (1H, s), 8.58 (1H, d), 8.18 (1H, d), 7.43 (1H, dd), 6.96 (1H, br.s), 3.28 (3H, s), 2.41 (3H, s), 1.23 (9H, s) A50

8.87 (1H, s), 8.54 (1H, d), 7.95 (1H, m), 3.27 (3H, s), 1.57-1.34 (9H,m) A51

8.88 (1H, br. s), 8.55 (1H, br. s), 8.06-7.82 (1H, m), 3.26 (3H, s),1.46 (9H, br. s) A52

8.87 (s, 1H), 8.53 (1H, d), 7.97 (1H, m), 3.24 (3H, s), 1.46 (9H, br. s)A61

9.14 (1H, s), 8.67 (1H, dd), 8.33-8.26 (3H, m), 7.39 (1H, dd), 7.23-2.33(2H, m), 3.40 (3H, s), 2.46 (3H, s) A62

8.55 (1H, s), 8.12 (1H, d), 7.54 (1H, dd), 3.21 (3H, s), 2.32 (3H, s),1.46 (9H, br. s) A63

8.57 (1H, s), 8.21 (1H, d), 7.63 (1H, d), 3.27 (3H, s), 1.44 (9H, s)

TABLE 4 Compounds of formula (I) Compound Structure Physical Data B1

9.08 (1H, d), 8.65 (1H, dd), 8.18 (1H, m), 7.38 (1H, dd), 4.72 (2H, br.s), 3.31 (3H, s), 2.51 (1H, br. s), 2.35 (3H, s) B2

9.09 (1H, d), 8.65 (1H, dd), 8.18 (1H, d), 7.38 (1H, dd), 5.43 (1H, br.s), 3.30 (3H, s), 2.51 (1H, br. s), 2.35 (3H, s), 1.45 (3H, br. s) B3

9.09 (1H, d), 8.64 (1H, dd), 8.18 (1H, d), 7.37 (1H, dd), 3.27 (3H, s),2.59 (1H, s), 2.5 (3H, s), 1.81-1.53 (6H, br. s) B10

8.87 (1H, s), 8.50 (1H, d), 7.95 (1H, d), 3.28 (3H, s), 2.59 (1H, s),2.35 (3H, s), 1.64 (6H, br. s) B11

8.87 (1H, s), 8.51 (1H, d), 7.95 (1H, m), 4.73 (2H, br. s), 3.30 (3H,s), 2.51 (1H, br. s), 2.36 (3H, s) B12

8.87 (1H, s), 8.50 (1H, d), 7.95 (1H, m), 4.70 (2H, br. s), 3.30 (3H,s), 2.35 (3H, s), 1.85 (3H, s)

BIOLOGICAL EXAMPLES B1 Pre-Emergence Herbicidal Activity

Seeds of a variety of test species were sown in standard soil in pots:Triticum aestivium (TRZAW), Oryza sativa (ORYSA), Avena fatua (AVEFA),Alopecurus myosuroides (ALOMY), Echinochloa crus-galli (ECHCG), Loliumperenne (LOLPE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH),Amaranthus retroflexus (AMARE) and Setaria faberi (SETFA). Aftercultivation for one day (pre-emergence) under controlled conditions in aglasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), theplants were sprayed with an aqueous spray solution derived from theformulation of the technical active ingredient in acetone/water (50:50)solution containing 0.5% Tween 20 (polyoxyethelyene sorbitanmonolaurate, CAS RN 9005-64-5). The test plants were then grown in aglasshouse under controlled conditions (at 24/16° C., day/night; 14hours light; 65% humidity) and watered twice daily. After 13 days, thetest was evaluated (5=total damage to plant; 0=no damage to plant).Results are shown in Tables 5 and 6.

B2 Post-Emergence Herbicidal Activity

Seeds of a variety of test species were sown in standard soil in pots:Triticum aestivium (TRZAW), Oryza sativa (ORYSA), Avena fatua (AVEFA),Alopecurus myosuroides (ALOMY), Echinochloa crus-galli (ECHCG), Loliumperenne (LOLPE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH),Amaranthus retroflexus (AMARE) and Setaria faberi (SETFA). After 8 dayscultivation (post-emergence) under controlled conditions in a glasshouse(at 24/16° C., day/night; 14 hours light; 65% humidity), the plants weresprayed with an aqueous spray solution derived from the formulation ofthe technical active ingredient in acetone/water (50:50) solutioncontaining 0.5% Tween 20 (polyoxyethelyene sorbitan monolaurate, CAS RN9005-64-5). The test plants were then grown in a glasshouse undercontrolled conditions (at 24/16° C., day/night; 14 hours light; 65%humidity) and watered twice daily. After 13 days, the test was evaluated(5=total damage to plant; 0=no damage to plant). Results are shown inTables 7 and 8.

TABLE 5 Control of weed species by compound of formula (I) afterpre-emergence application at a rate of 1000 g/Ha Com- pound ORYSA TRZAWALOMY AVEFA LOLPE ECHCG A1 2 2 2 4 2 4 A2 1 0 0 3 2 5 A3 1 1 1 3 2 4 A40 0 1 4 2 4 A5 0 0 0 0 0 0 A6 1 0 1 0 1 2 A7 1 1 1 4 2 2 A8 0 0 0 0 0 0A9 0 0 0 0 0 0 A10 1 1 0 1 1 1 A11 2 2 1 1 0 2 A12 0 0 0 3 1 3 A13 1 0 00 0 1 A14 0 1 0 0 1 0 A15 0 0 0 0 0 0 A16 1 3 0 3 4 4 A17 0 0 0 0 0 0A18 0 1 1 2 2 5 A19 0 0 1 1 1 5 A20 0 0 0 2 2 5 A21 0 0 0 2 1 5 A22 0 00 0 0 0 A23 0 0 0 0 0 0 A24 0 1 2 4 3 4 A25 1 0 1 4 3 4 A26 1 0 2 4 3 4A27 0 0 0 2 2 2 A28 0 0 0 1 2 3 A29 2 3 1 2 2 3 A30 1 0 1 3 2 4 A31 1 11 1 2 3 A32 2 0 0 1 1 2 A38 3 0 1 1 2 5 A45 2 1 2 3 2 3 A51 0 0 0 2 3 1A52 1 0 0 3 3 2 A62 1 1 2 2 2 3 A63 0 0 0 1 1 1

TABLE 6 Control of weed species by compound of formula (I)-(i) afterpre-emergence application at a rate of 1000 g/Ha Com- pound ZEAMX ABUTHSETFA AMARE LOLPE ECHCG B1 5 2 5 2 3 2 B2 5 3 5 3 3 1 B3 5 4 4 3 3 3

TABLE 7 Control of weed species by compound of formula (I) afterpost-emergence application at a rate of 1000 g/Ha Com- pound TRZAW ORYSAAVEFA ALOMY ECHCG LOLPE A1 0 1 4 0 4 4 A2 1 1 5 1 5 3 A3 1 1 4 1 5 3 A41 1 5 0 4 2 A5 0 0 0 0 0 0 A6 1 0 2 1 4 2 A7 2 1 4 1 5 3 A8 2 1 2 1 3 0A9 2 1 2 1 2 1 A10 1 1 2 0 4 0 A11 2 1 1 1 2 1 A12 2 1 2 0 4 3 A13 2 1 01 2 0 A14 0 0 0 0 1 0 A15 1 0 2 0 1 1 A16 4 0 5 3 5 4 A17 1 2 4 1 1 2A18 1 0 3 1 5 2 A19 1 0 3 1 5 2 A20 1 0 3 1 5 3 A21 1 0 4 2 5 3 A22 0 02 0 2 2 A23 0 0 1 0 1 0 A24 1 2 4 0 5 4 A25 2 1 4 1 5 4 A26 1 2 5 0 5 4A27 2 1 4 1 5 3 A28 1 1 2 1 4 3 A29 1 1 4 1 5 4 A30 2 1 4 1 5 4 A31 1 15 1 4 3 A32 0 1 3 1 3 2 A35 1 0 1 0 2 0 A38 1 0 4 1 5 3 A45 2 2 5 1 4 4A51 0 0 4 0 4 2 A52 1 0 4 1 4 3 A61 1 0 2 0 1 1 A62 1 0 4 1 4 4 A63 0 03 1 5 2

TABLE 8 Control of weed species by compound of formula (I)-(i) afterpost-emergence application at a rate of 1000 g/Ha Com- pound SETFA ZEAMXECHCG LOLPE AMARE ABUTH B1 5 5 4 3 1 1 B2 5 4 2 4 2 2 B3 5 5 4 4 2 1

1. A method of controlling unwanted plant growth, comprising applying acompound of formula (I)

or a salt or N-oxide thereof, wherein, X₁ is N or CR¹; R¹ is hydrogen,halogen, cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, —C(O)OR⁶ or S(O)_(n)(C₁-C₆alkyl), formyl, hydroxyl,—C(O)NR⁶R⁷, NR⁶R⁷, benzyloxy, C₁-C₆ haloalkoxy, or C₁-C₆ haloalkyl; R²is hydrogen, halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, —C(O)OR⁶,S(O)_(n)(C₁-C₆alkyl), C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; n is 0, 1, or2; R³ is hydrogen, cyano, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₂-C₆haloalkenyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy,C₂-C₆alkenyloxy, C₃-C₁₀cycloalkyl, NR⁶R⁷, R⁴ is O, S, or N(C₁-C₆alkyl);X₂ is O, S, or NR⁸; R⁵ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkenyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₆alkenyloxy,C₂-C₆alkynyloxy, C₃-C₁₀cycloalkyloxy, C₃-C₁₀cycloalkenyloxy,C₂-C₆haloalkenyloxy, C₆-C₁₀aryl or C₆-C₁₀aryl substituted by from 1 to 3groups independently selected from halogen, nitro, cyano, C₁-C₃ alkyl,C₁-C₃ alkoxy, C₁-C₃ haloalkyl, and C₁-C₃ haloalkoxy; C₃-C₁₀heterocylcylor C₃-C₁₀heterocyclycl substituted by from 1 to 3 groups independentlyselected from halogen, nitro, cyano, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃haloalkyl, and C₁-C₃ haloalkoxy; or NR⁶R⁷; or R³ and R⁵ together with X₂and the atoms to which they are attached, form a saturated or partiallyunsaturated 5-9 membered ring system optionally comprising 1 to 3heteroatoms independently selected from S, O and N and optionallysubstituted with 1 to 3 groups independently selected from halogen orC₁-C₆ alkyl; or R³ and R⁸ together with the atoms to which they areattached form a saturated or partially unsaturated 5-9 membered ringsystem optionally comprising 1 to 3 heteroatoms independently selectedfrom S, O and N and optionally substituted with 1 to 3 groupsindependently selected from halogen or C₁-C₆ alkyl; R⁶ and R⁷ are eachindependently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, or R⁴ and R⁵ together with X₂ and the atoms to which theyare attached, form a saturated or partially unsaturated 5-9 memberedring system optionally comprising 1 to 3 heteroatoms independentlyselected from S, O and N and optionally substituted with 1 to 3 groupsindependently selected from halogen or C₁-C₆ alkyl; or R⁶ and R⁷together with the nitrogen atom to which they are attached form asaturated or partially unsaturated 3-6 membered ring optionallycomprising 1 to 3 heteroatoms independently selected from S, O and N andoptionally substituted with 1 to 3 groups independently selected fromhalogen or C₁-C₆ alkyl; R⁸ is hydrogen, cyano, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; C₁-C₆alkoxy,C₁-C₆haloalkoxy, C₂-C₆alkenyloxy, C₂-C₆alkynyloxy, C₃-C₁₀cycloalkyloxy,C₃-C₁₀cycloalkenyloxy, C₂-C₆haloalkenyloxy; or R⁷ and R⁸ together withthe carbon atoms to which they are attached form a saturated orpartially unsaturated 3-9 membered ring optionally comprising 1 to 3heteroatoms independently selected from S, O and N and optionallysubstituted with 1 to 3 groups independently selected from halogen orC₁-C₆ alkyl, to the unwanted plants or to the locus thereof.
 2. Themethod according to claim 1, wherein R¹ is hydrogen, halogen, formyl,cyano, C₁-C₆ alkoxy, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio, C₁-C₆haloalkoxy, —C(O)NR⁶R⁷, NR⁶R⁷, or C₁-C₆ haloalkyl
 3. (canceled)
 4. Themethod according to claim 1, wherein R² is halogen, cyano, nitro, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, —C(O)OR⁶, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₃-C₆ cycloalkyl, or C₂-C₆ alkynyl
 5. (canceled)
 6. Themethod according to claim 1 wherein R³ is C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₂-C₆ haloalkenyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C₂-C₆ alkenyloxy, C₃-C₁₀ cycloalkyl, or NR⁶R⁷.
 7. (canceled)8. The method according to claim 1 wherein R⁵ is C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ haloalkyl, C₂-C₆haloalkenyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₃-C₁₀ cycloalkyloxy, C₃-C₁₀ cycloalkenyloxy, C₂-C₆haloalkenyloxy, C₆-C₂₀ aryl, C₃-C₂₀ heterocylcyl, or NR⁶R⁷.
 9. Themethod according to claim 1, wherein R³ and R⁵ together with X₂ and theatoms to which they are attached, form a ring system Q, selected fromthe group consisting of Q₁ and Q₂,

wherein X² and R⁴ are as defined in claim 1, and A denotes the point ofattachment to the pyridino/pyrimidino-thiazole moiety.
 10. (canceled)11. The method according to claim 1 wherein R⁴ is O.
 12. The methodaccording to claim 1 wherein X₂ is O, or NR⁸.
 13. (canceled) 14.(canceled)
 15. (canceled)
 16. A herbicidal composition comprising from0.1 to 99% by weight, of a compound of Formula (I) as defined in claim1, and from 1 to 99.9% by weight of a formulation adjuvant, wherein theformulation adjuvant comprises from 0 to 25% by weight of asurface-active substance.
 17. (canceled)
 18. The herbicidal compositionof claim 16, further comprising at least one additional pesticideselected from a herbicide or herbicide safener.
 19. (canceled) 20.(canceled)
 21. A method of selectively controlling weeds at a locuscomprising crop plants and weeds, wherein the method comprisesapplication to the locus, of a weed-controlling amount of (i) a compoundof formula (I):

or a salt or N-oxide thereof, wherein, X₁ is N or CR¹; R¹ is hydrogen,halogen, cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, —C(O)OR⁶ or S(O)_(n)(C₁-C₆alkyl), formyl, hydroxyl,—C(O)NR⁶R⁷, NR⁶R⁷, benzyloxy, C₁-C₆ haloalkoxy, or C₁-C₆ haloalkyl; R²is hydrogen, halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, —C(O)OR⁶,S(O)_(n)(C₁-C₆alkyl), C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; n is 0, 1, or2; R³ is hydrogen, cyano, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₂-C₆haloalkenyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy,C₂-C₆alkenyloxy, C₃-C₁₀cycloalkyl, NR⁶R⁷, R⁴ is O, S, or N(C₁-C₆alkyl);X₂ is O, S, or NR⁸; R⁵ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀cycloalkenyl, C₁-C₆haloalkyl,C₂-C₆haloalkenyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₆alkenyloxy,C₂-C₆alkynyloxy, C₃-C₁₀cycloalkyloxy, C₃-C₁₀cycloalkenyloxy,C₂-C₆haloalkenyloxy, C₆-C₁₀aryl or C₆-C₁₀aryl substituted by from 1 to 3groups independently selected from halogen, nitro, cyano, C₁-C₃ alkyl,C₁-C₃ alkoxy, C₁-C₃ haloalkyl, and C₁-C₃ haloalkoxy; C₃-C₁₀heterocylcylor C₃-C₁₀heterocyclycl substituted by from 1 to 3 groups independentlyselected from halogen, nitro, cyano, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃haloalkyl, and C₁-C₃ haloalkoxy; or NR⁶R⁷; or R³ and R⁵ together with X₂and the atoms to which they are attached, form a saturated or partiallyunsaturated 5-9 membered ring system optionally comprising 1 to 3heteroatoms independently selected from S, O and N and optionallysubstituted with 1 to 3 groups independently selected from halogen orC₁-C₆ alkyl; or R³ and R⁸ together with the atoms to which they areattached form a saturated or partially unsaturated 5-9 membered ringsystem optionally comprising 1 to 3 heteroatoms independently selectedfrom S, O and N and optionally substituted with 1 to 3 groupsindependently selected from halogen or C₁-C₆ alkyl; R⁶ and R⁷ are eachindependently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, or R⁴ and R⁵ together with X₂ and the atoms to which theyare attached, form a saturated or partially unsaturated 5-9 memberedring system optionally comprising 1 to 3 heteroatoms independentlyselected from S, O and N and optionally substituted with 1 to 3 groupsindependently selected from halogen or C₁-C₆ alkyl; or R⁶ and R⁷together with the nitrogen atom to which they are attached form asaturated or partially unsaturated 3-6 membered ring optionallycomprising 1 to 3 heteroatoms independently selected from S, O and N andoptionally substituted with 1 to 3 groups independently selected fromhalogen or C₁-C₆ alkyl; R⁸ is hydrogen, cyano, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; C₁-C₆alkoxy,C₁-C₆haloalkoxy, C₂-C₆alkenyloxy, C₂-C₆alkynyloxy, C₃-C₁₀cycloalkyloxy,C₃-C₁₀cycloalkenyloxy, C₂-C₆haloalkenyloxy; or R⁷ and R⁸ together withthe carbon atoms to which they are attached form a saturated orpartially unsaturated 3-9 membered ring optionally comprising 1 to 3heteroatoms independently selected from S, O and N and optionallysubstituted with 1 to 3 groups independently selected from halogen orC₁-C₆ alkyl.